Bicyclic oxopyridine and oxopyrimidine derivatives

ABSTRACT

Compounds of formulae (1a) and (1b) are described: in which the dashed line represents an optional bond; A is a —N=atom or a —N(R b )—, —C(R b )═ or —C(R b )(R C )— group; R a , R b  and R c  is each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group; X is an —O— or —S— atom or —NH— group or substituted N atom; each Y is independently a N atom or CH group or substituted C atom; n is zero or the integer 1; Alk 1  is an optionally substituted aliphatic or heteroaliphatic chain L 1  is a covalent bond or a linker atom or group; Cy 1  is a hydrogen atom or an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group; Ar is an optionally substituted aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof; The compounds are potent inhibitors of p38 kinase and are use in the prophylaxis or treatment of p38 kinase mediated diseases or disorders, such as rheumatoid arthritis.

[0001] This invention relates to a series of 5-6 fused ring bicyclicheteroaromatic derivatives, to compositions containing them, toprocesses for their preparation and to their use in medicine.

[0002] Immune and inflammatory responses involve a variety of cell typeswith control and co-ordination of the various interactions occurring viaboth cell-cell contacts (e.g integrin interactions with their receptors)and by way of intercellular signalling molecules. A large number ofdifferent signalling molecules are involved including cytokines,lymphocytes, chemokines and growth factors.

[0003] Cells respond to such intercellular signalling molecules by meansof intracellular signalling mechanisms that include protein kinases,phosphatases and phospholipases. There are five classes of proteinkinase of which the major ones are the tyrosine kinases and theserine/threonine kinases [Hunter, T., Methods in Enzymology (ProteinKinase Classification) p. 3, Hunter, T. and Sefton, B. M.; eds. Vol.200, Academic Press; San Diego, 1991].

[0004] One sub-class of serine/threonine kinases is the mitogenactivating protein (MAP) kinases of which there are at least threefamilies which differ in the sequence and size of the activation loop[Adams, J. L. et al, Progress in Medicinal Chemistry p. 1-60, King, F.D. and Oxford, A. W.; eds. vol 38, Elsevier Science, 2001]: theextracellular regulated kinases (ERKs), the c-Jun NH₂ terminal kinasesor stress activated kinases (JNKs or SAP kinases) and the p38 kinaseswhich have a threonine-glycine-tyrosine (TGY) activation motif. Both theJNKs and p38 MAP kinases are primarily activated by stress stimuliincluding, but not limited to, proinflammatory cytokines e.g. tumournecrosis factor (TNF) and interleukin-1 (IL-1), ultraviolet light,endotoxin and chemical or osmotic shock.

[0005] Four isoforms of p38 have been described (p38α/β/γ/δ). The humanp38α enzyme was initially identified as a target of cytokine-suppressiveanti-inflammatory drugs (CSAIDs) and the two isoenzymes found wereinitially termed CSAID binding protein-1 (CSBP-1) and CSBP-2 [Lee, J. C.et al, Nature (London) 1994, 372, 739-46]. CSBP-2 is now widely referredto as p38α and differs from CSBP-1 in an internal sequence of 25 aminoacids as a result of differential splicing of two exons that areconserved in both mouse and human [McDonnell, P. C. et al, Genomics1995, 29, 301-2]. CSBP-1 and p38α are expressed ubiquitously and thereis no difference between the two isoforms with respect to tissuedistribution, activation profile, substrate preference or CSAID binding.A second isoform is p38β which has 70% identity with p38α. A second formof p38β termed p38β2 is also known and of the two this is believed to bethe major form. p38α and p38β2 are expressed in many different tissues.However in monocytes and macrophages p38α is the predominant kinaseactivity [Lee, J. C., ibid; Jing, Y. et al, J. Biol. Chem. 1996, 271,10531-34; Hale, K. K. et al, J. Immun. 1999, 162, 4246-52]. p38γ andp38δ (also termed SAP kinase-3 and SAP kinase-4 respectively) have ˜63%and ˜61% homology to p38α respectively. p38δ is predominantly expressedin skeletal muscle whilst p38δ is found in testes, pancreas, prostate,small intestine and in certain endocrine tissues.

[0006] All p38 homologues and splice variants contain a 12 amino acidactivation loop that includes a Thr-Gly-Tyr motif. Dual phosphorylationof both Thr-180 and Tyr-182 in the TGY motif by a dual specificityupstream kinase is essential for the activation of p38 and results ina >1000-fold increase in specific activity of these enzymes [Doza, Y. N.et al FEBS Lett., 1995, 364, 7095-8012]. This dual phosphorylation iseffected by MKK6 and under certain conditions the related enzyme MKK3(see FIG. 1) [Enslen, H. et al J. Biol. Chem., 1998, 273,1741-48]. MKK3and MKK6 belong to a family of enzymes termed MAPKK (mitogen activatingprotein kinase kinase) which are in turn activated by MAPKKK (mitogenactivating kinase kinase kinase) otherwise known as MAP3K.

[0007] Several MAP3Ks have been identified that are activated by a widevariety of stimuli including environmental stress, inflammatorycytokines and other factors. MEKK4/MTK1 (MAP or ERK kinase kinase/MAPthree kinase-1), ASK1 (apoptosis stimulated kinase) and TAK1(TGF-β-activated kinase) are some of the enzymes identified as upstreamactivators of for MAPKKs. MEKK4/MTK1 is thought to be activated byseveral GADD-45-like genes that are induced in response to environmentalstimuli and which eventually lead to p38 activation [Takekawa, M. andSaito, H. Cell, 1998, 95, 521-30]. TAK1 has been shown to activate MKK6in response to transforming growth factor-β (TGF-β). TNF-stimulatedactivation of p38 is believed to be mediated by the recruitment of TRAF2[TNF receptor associated factor] and the Fas adaptor protein, Daxx,which results in the activation of ASK1 and subsequently p38.

[0008] Several substrates of p38 have been identified including otherkinases [e.g. MAPK activated protein kinase 2/3/5 (MAPKAP 2/3/5), p38regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase1/2 (MNK1/2), mitogen- and stress-activated protein kinase 1 (MSK1/RLPK)and ribosomal S6 kinase-B (RSK-B)], transcription factors [e.g.activating transcription factor 2/6 (ATF2/6), monocyte-enhancerfactor-2A/C (MEF2A/C), C/EBP homologous protein (CHOP), Elk1 andSap-1a1] and others substrates [e.g. cPLA2, p47phox].

[0009] MAPKAP K2 is activated by p38 in response to environmentalstress. Mice engineered to lack MAPKAP K2 do not produce TNF in responseto lipopolysaccharide (LPS). Production of several other cytokines suchas IL-1, IL-6, IFN-g and IL-10 is also partially inhibited [Kotlyarov,A. et al Nature Cell Biol. 1999, 1, 94-7]. Further, MAPKAP K2 fromembryonic stem cells from p38α null mice was not activated in responseto stress and these cells did not produce IL-6 in response to IL-1[Allen, M. et al, J. Exp. Med. 2000, 191, 859-69]. These resultsindicate that MAPKAP K2 is not only essential for TNF and IL-1production but also for signalling induced by cytokines. In additionMAPKAP K2/3 phosphorylate and thus regulate heat shock proteins HSP 25and HSP 27 which are involved in cytoskeletal reorganization.

[0010] Several small molecule inhibitors of p38 have been reported whichinhibit IL-1 and TNF synthesis in human monocytes at concentrations inthe low μM range [Lee, J. C. et al, Int. J. Immunopharm. 1988, 10, 835]and exhibit activity in animal models which are refractory tocyclooxygenase inhibitors [Lee, J. C. et al, Annals N. Y. Acad. Sci.1993, 696, 149]. In addition these small molecule inhibitors are knownto also decrease the synthesis of a wide variety of pro-inflammatoryproteins including IL-6, IL-8, granulocyte/macrophage colony-stimulatingfactor (GM-CSF) and cyclooxygenase-2 (COX-2). TNF-inducedphosphorylation and activation of cytosolic PLA2, TNF-induced expressionof VCAM-1 on endothelial cells and IL-1 stimulated synthesis ofcollagenase and stromelysin are also inhibited by such small moleculeinhibitors of p38 [Cohen, P. Trends Cell Biol. 1997, 7, 353-61].

[0011] A variety of cells including monocytes and macrophages produceTNF and IL-1. Excessive or unregulated TNF production is implicated in anumber of disease states including Crohn's disease, ulcerative colitis,pyresis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic conditions, toxic shock syndrome,endotoxic shock, sepsis, septic shock, gram negative sepsis, boneresporption diseases, reperfusion injury, graft vs. host reaction,allograft rejection, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoisosis,cerebral malaria, scar tissue formation, keloid formation, fever andmyalgias due to infection, such as influenza, cachexia secondary toacquired immune deficiency syndrome (AIDS), cachexia secondary toinfection or malignancy, AIDS or AIDS related complex.

[0012] Excessive or unregulated IL-1 production has been implicated inrheumatoid arthritis, osteoarthritis, traumatic arthritis, rubellaarthritis, acute synovitis, psoriatic arthritis, cachexia, Reiter'ssyndrome, endotoxemia, toxic shock syndrome, tuberculosis,atherosclerosis, muscle degeneration, and other acute or chronicinflammatory diseases such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease. In addition IL-1 has beenlinked to diabetes and pancreatic β cells [Dinarello, C. A. J. ClinicalImmunology, 1985, 5, 287-97].

[0013] IL-8 is a chemotactic factor produced by various cell typesincluding endothelial cells, mononuclear cells, fibroblasts andkeratinocytes. IL-1, TNF and LPS all induce the production of IL-8 byendothelial cells. In vitro IL-8 has been shown to have a number offunctions including being a chemoattractant for neutrophils,T-lymphocytes and basophils. IL-8 has also been shown to increase thesurface expression of Mac-1 (CD11b/CD18) on neutrophils without de novoprotein synthesis which may contribute to increased adhesion ofneutrophils to vascular endothelial cells. Many diseases arecharacterised by massive neutrophil infiltration. Histamine release frombasophils (in both atopic and normal individuals) is induced by IL-8 asis lysozomal enzyme release and respiratory burst from neutrophils.

[0014] The central role of IL-1 and TNF together with other leukocytederived cytokines as important and critical inflammatory mediators iswell documented. The inhibition of these cytokines has been shown orwould be expected to be of benefit in controlling, alleviating orreducing many of these disease states.

[0015] The central position that p38 occupies within the cascade ofsignalling molecules mediating extracellular to intracellular signallingand its influence over not only IL-1, TNF and IL-8 production but alsothe synthesis and/or action of other pro-inflammatory proteins (e.g.IL-6, GM-CSF, COX-2, collagenase and stromelysin) make it an attractivetarget for inhibition by small molecule inhibitors with the expectationthat such inhibition would be a highly effective mechanism forregulating the excessive and destructive activation of the immunesystem. Such an expectation is supported by the potent and diverseanti-inflammatory activities described for p38 kinase inhibitors [Adams,ibid; Badger, et al, J. Pharm. Exp. Ther. 1996, 279, 1453-61; Griswold,et al, Pharmacol. Comm., 1996, 7, 323-29].

[0016] Japanese patent application No. JP09059276 describes a series ofpyrazalopyridinones and analogs with utility as herbicides.

[0017] We have now found a group of compounds which are potent andselective inhibitors of p38 kinase (p38α, β, δ and γ) and the isoformsand splice variants thereof, especially p38α, p38β and p38β2. Thecompounds are thus of use in medicine, for example in the prophylaxisand treatment of immune or inflammatory disorders as described herein.

[0018] Thus according to one aspect of the invention we provide acompound of formula (1a) or (1b):

[0019] wherein:

[0020] the dashed line represents an optional bond;

[0021] A is a —N═ atom or a —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))—group;

[0022] R^(a), R^(b) and R^(c) is each independently a hydrogen atom oran optionally substituted C₁₋₆alkyl group;

[0023] X is an —O— or —S— atom or —NH— group or substituted N atom;

[0024] each Y is independently a N atom or CH group or substituted Catom; n is zero or the integer 1;

[0025] Alk¹ is an optionally substituted aliphatic or heteroaliphaticchain L¹ is a covalent bond or a linker atom or group;

[0026] Cy¹ is a hydrogen atom or an optionally substitutedcycloaliphatic, polycycloaliphatic, heterocycloaliphatic,polyheterocycloaliphatic, aromatic or heteroaromatic group;

[0027] Ar is an optionally substituted aromatic or heteroaromatic group;

[0028] and the salts, solvates, hydrates and N-oxides thereof;

[0029] for the manufacture of a medicament for the prophylaxis ortreatment of a p38 kinase mediated disease or disorder.

[0030] This invention also relates to a compound of formula (1a) or (1b)for use in the prophylaxis or treatment of a p38 kinase mediated diseaseor disorder in a mammal in need thereof.

[0031] This invention also relates to a compound of formula (1a) or (1b)for use in the prophylaxis or treatment of a cytokine mediated diseaseor disorder in a mammal in need thereof.

[0032] This invention more specifically relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof.

[0033] This invention more specifically relates to a method ofinhibiting the production of IL-6 in a mammal in need thereof.

[0034] This invention more specifically relates to a method ofinhibiting the production of IL-8 in a mammal in need thereof.

[0035] This invention more specifically relates to a method ofinhibiting the production of TNF in a mammal in need thereof.

[0036] This invention more specifically relates to the administration toa mammal of an effective amount of a p38 kinase or cytokine,specifically IL-1, IL-6, IL-8 or TNF, inhibitor of formula (1a) or (1b).

[0037] Compounds according to the invention are potent and selectiveinhibitors of p38 kinases, including all isoforms and splice variantsthereof. More specifically the compounds of the invention are inhibitorsof p38α, p38β and p38β2. The ability of the compounds to act in this waymay be simply determined by employing tests such as those described inthe Examples hereinafter.

[0038] The compounds of formula (1) are of use in modulating theactivity of p38 kinases and in particular are of use in the prophylaxisand treatment of any p38 kinase mediated diseases or disorders in ahuman, or other mammal. The invention extends to such a use and to theuse of the compounds for the manufacture of a medicament for treatingsuch diseases or disorders. Further the invention extends to theadministration to a human an effective amount of a p38 inhibitor fortreating any such disease or disorder.

[0039] The invention also extends to the prophylaxis or treatment of anydisease or disorder in which p38 kinase plays a role includingconditions caused by excessive or unregulated pro-inflammatory cytokineproduction including for example excessive or unregulated TNF, IL-1,IL-6 and IL-8 production in a human, or other mammal. The inventionextends to such a use and to the use of the compounds for themanufacture of a medicament for treating such cytokine-mediated diseasesor disorders. Further the invention extends to the administration to ahuman an effective amount of a p38 inhibitor for treating any suchdisease or disorder.

[0040] Diseases or disorders in which p38 kinase plays a role eitherdirectly or via pro-inflammatory cytokines including the cytokines TNF,IL-1, IL-6 and IL-8 include without limitation autoimmune diseases,inflammatory diseases, destructive-bone disorders, proliferativedisorders, neurodegenerative disorders, viral diseases, allergies,infectious diseases, heart attacks, angiogenic disorders,reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia,cardiac hypertrophy, thrombin-induced platelet aggregation andconditions associated with prostaglandin endoperoxidase synthetase-2(COX-2).

[0041] Autoimmune diseases which may be prevented or treated include butare not limited to rheumatoid arthritis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, multiple sclerosis, diabetes,glomerulonephritis, systemic lupus erythematosus, scleroderma, chronicthyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis,autoimmune neutropenia, thrombocytopenia, chronic active hepatitis,myasthenia gravis, atopic dermatitis, graft vs, host disease orpsoriasis.

[0042] The invention further extends to the particular autoimmunedisease rheumatoid arthritis.

[0043] Inflammatory diseases which may be prevented or treated includebut are not limited to asthma, allergies, respiratory distress syndromeor acute or chronic pancreatitis.

[0044] Destructive bone disorders which may be prevented or treatedinclude but are not limited to osteoporosis, osteoarthritis and multiplemyeloma-related bone disorder.

[0045] Proliferative diseases which may be prevented or treated includebut are not limited to acute or chronic myelogenous leukemia, Kaposi'ssarcoma, metastic melanoma and multiple myeloma.

[0046] Neurodegenerative diseases which may be prevented or treatedinclude but are not limited to Parkinson's disease, Alzheimer's disease,cerebral ischemias or neurodegenerative disease caused by traumaticinjury.

[0047] Viral diseases which may be prevented or treated include but arenot limited to acute hepatitis infection (including hepatitis A,hepatitis B and hepatitis C), HIV infection and CMV retinitis.

[0048] Infectious diseases which may be prevented or treated include butare not limited to septic shock, sepsis and Shigellosis.

[0049] In addition, p38 inhibitors of this invention also exhibitinhibition of expression of inducible pro-inflammatory proteins such asprostaglandin endoperoxidase synthetase-2, otherwise known ascyclooxygenase-2 (COX-2) and are therefore of use in therapy.Pro-inflammatory mediators of the cyclooxygenase pathway derived fromarachidonic acid are produced by inducible COX-2 enzyme. Regulation ofCOX-2 would regulate these pro-inflammatory mediators such asprostaglandins, which affect a wide variety of cells and are importantand critical inflammatory mediators of a wide variety of disease statesand conditions. In particular these inflammatory mediators have beenimplicated in pain, such as in the sensitization of pain receptors, oredema. Accordingly additional p38 mediated conditions which may beprevented or treated include edema, analgesia, fever and pain such asneuromuscular pain, headache, dental pain, arthritis pain and paincaused by cancer.

[0050] As a result of their p38 inhibitory activity, compounds of theinvention have utility in the prevention and treatment of diseasesassociated with cytokine production including but not limited to thosediseases associated with TNF, IL-1, IL-6 and IL-8 production.

[0051] Thus TNF mediated diseases or conditions include for examplerheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, sepsis, septic shock syndrome,adult respiratory distress syndrome, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoiosis, bone resportiondisease, reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection, cachexia secondary toinfection, AIDS, ARC or malignancy, keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, pyresis, viralinfections such as HIV, CMV, influenza and herpes; and vetinary viralinfections, such as lentivirus infections, including but not limited toequine infectious anemia virus, caprine arthritis virus, visna virus ormaedi virus; or retrovirus infections, including feline immunodeficiencyvirus, bovine immunodeficiency virus or canine immunodeficiency virus.

[0052] Compounds of the invention may also be used in the treatment ofviral infections, where such viruses elicit TNF production in vivo orare sensitive to upregulation by TNF. Such viruses include those thatproduce TNF as a result of infection and those that are sensitive toinhibition, for instance as a result of decreased replication, directlyor indirectly by the TNF inhibiting compounds of the invention. Suchviruses include, but are not limited to, HIV-1, HIV-2 and HIV-3,Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group ofviruses such as Herpes Zoster and Herpes Simplex.

[0053] IL-1 mediated diseases or conditions include for examplerheumatoid arthritis, osteoarthritis, psoriatic arthritis, traumaticarthritis, rubella arthritis, inflammatory bowel disease, stroke,endotoxemia and/or toxic shock syndrome, inflammatory reaction inducedby endotoxin, diabetes, pancreatic β-cell disease, Alzheimer's disease,tuberculosis, atherosclerosis, muscle degeneration and cachexia.

[0054] IL-8 mediated diseases and conditions include for example thosecharacterized by massive neutrophil infiltration such as psoriasis,inflammatory bowel disease, asthma, cardiac, brain and renal reperfusioninjury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. The increased IL-8 production associated with eachof these diseases is responsible for the chemotaxis of neutrophils intoinflammatory sites. This is due to the unique property of IL-8 (incomparison to TNF, IL-1 and IL-6) of promoting neutrophil chemotaxis andactivation. Therefore, inhibition of IL-8 production would lead to adirect reduction in neutrophil infiltration.

[0055] It is also known that both IL-6 and IL-8 are produced duringrhinovirus (HRV) infections and contribute to the pathogenesis of thecommon cold and exacerbation of asthma associated with HRV infection[Turner et al, Clin. Infec. Dis., 1997, 26, 840; Grunberg et al, Am. J.Crit. Care Med. 1997, 155, 1362; Zhu et al, J. Clin. Invest. 1996, 97,421]. It has also been demonstrated in vitro that infection of pulmonaryepithelial cells (which represent the primary site of infection by HRV)with HRV results in production of IL-6 and IL-8 [Sabauste et al, J.Clin. Invest. 1995, 96, 549]. Therefore, p38 inhibitors of the inventionmay be used for the treatment or prophylaxis of the common cold orrespiratory viral infection caused by human rhinovirus infection (HRV),other enteroviruses, coronavirus, influenza virus, parainfluenza virus,respiratory syncytial virus or adenovirus infection.

[0056] For the prophylaxis or treatment of a p38 or pro-inflammatorycytokine mediated disease the compounds according to the invention maybe administered to a human or mammal as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1a) or(1b) together with one or more pharmaceutically acceptable carriers,excipients or diluents.

[0057] Pharmaceutical compositions according to the invention may take aform suitable for oral, buccal, parenteral, nasal, topical, ophthalmicor rectal administration, or a form suitable for administration byinhalation or insufflation.

[0058] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

[0059] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0060] For buccal administration the compositions may take the form oftablets or lozenges formulated in conventional manner.

[0061] The compounds of formula (1a) or (1b) may be formulated forparenteral administration by injection e.g. by bolus injection orinfusion. Formulations for injection may be presented in unit dosageform, e.g. in glass ampoule or multi dose containers, e.g. glass vials.The compositions for injection may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising, preserving and/ordispersing agents. Alternatively, the active ingredient may be in powderform for constitution with a suitable vehicle, e.g. sterile pyrogen-freewater, before use.

[0062] In addition to the formulations described above, the compounds offormula (1a) or (1b) may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation or byintramuscular injection.

[0063] For nasal administration or administration by inhalation, thecompounds for lo use according to the present invention are convenientlydelivered in the form of an aerosol spray presentation for pressurisedpacks or a nebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

[0064] The compositions may, if desired, be presented in a pack ordispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack or dispensing device may beaccompanied by instructions for administration.

[0065] For topical administration the compounds for use according to thepresent invention may be conveniently formulated in a suitable ointmentcontaining the active component suspended or dissolved in one or morepharmaceutically acceptable carriers. Particular carriers include, forexample, mineral oil, liquid petroleum, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively the compounds for use according to the present inventionmay be formulated in a suitable lotion containing the active componentsuspended or dissolved in one or more pharmaceutically acceptablecarriers. Particular carriers include, for example mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzylalcohol, 2-octyidodecanol and water.

[0066] For ophthalmic administration the compounds for use according tothe present invention may be conveniently formulated as microionizedsuspensions in isotonic, pH adjusted sterile saline, either with orwithout a preservative such as bactericidal or fungicidal agent, forexample phenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

[0067] For rectal administration the compounds for use according to thepresent invention may be conveniently formulated as suppositories. Thesecan be prepared by mixing the active component with a suitablenon-irritating excipient which is solid at room temperature but liquidat rectal temperature and so will melt in the rectum to release theactive component. Such materials include for example cocoa butter,beeswax and polyethylene glycols.

[0068] The quantity of a compound of the invention required for theprophylaxis or treatment of a particular condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 100 ng/kg to100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral orbuccal administration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

[0069] Particular compounds of formula (1a) and formula (1b) form afurther aspect of the invention. Thus we provide a compound of formula(1a):

[0070] wherein:

[0071] the dashed line represents an optional bond;

[0072] A is a —N═ atom or a —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))—group;

[0073] R^(a), R^(b) and R^(c) is each independently a hydrogen atom oran optionally substituted C₁₋₆alkyl group;

[0074] X is an —O— or —S— atom or —NH— group or substituted N atom;

[0075] Y is a N atom or CH group or substituted C atom;

[0076] n is zero or the integer 1;

[0077] Alk¹ is an optionally substituted aliphatic or heteroaliphaticchain L¹ is a covalent bond or a linker atom or group;

[0078] Cy¹ is a hydrogen atom or an optionally substitutedcycloaliphatic, polycycloaliphatic, heterocycloaliphatic,polyheterocycloaliphatic, aromatic or heteroaromatic group;

[0079] Ar is an optionally substituted aromatic or heteroaromatic group;

[0080] and the salts, solvates, hydrates and N-oxides thereof;

[0081] Particular compounds of formula (1a) in which Cy¹ is anoptionally substituted cycloaliphatic, polycycloaliphatic,heterocycloaliphatic, polyheterocycloaliphatic, aromatic orheteroaromatic group form a further aspect of the invention.

[0082] In another particular aspect of the invention and we provide acompound of formula (1b):

[0083] wherein:

[0084] the dashed line represents an optional bond;

[0085] A is a —N═ atom or a —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))—group;

[0086] R^(a), R^(b) and R^(c) is each independently a hydrogen atom oran optionally substituted C₁₋₆alkyl group;

[0087] each Y is independently a N atom or CH group or substituted Catom;

[0088] n is zero or the integer 1;

[0089] Alk¹ is an optionally substituted aliphatic or heteroaliphaticchain L¹ is a covalent bond or a linker atom or group;

[0090] Cy¹ is a hydrogen atom or an optionally substitutedcycloaliphatic, polycycloaliphatic, heterocycloaliphatic,polyheterocycloaliphatic, aromatic or heteroaromatic group;

[0091] Ar is an optionally substituted aromatic or heteroaromatic group;

[0092] and the salts, solvates, hydrates and N-oxides thereof;

[0093] with the proviso that when the compound of formula (1b) is acompound of formula (1c):

[0094] in which

[0095] each Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl or2-chloro-6-fluoro-4-trifluoromethylphenyl group, L¹ is a covalent bond,n is the integer 1 and Alk¹ is a —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)CH₂—, —CH₂CH═CH—, —CH₂CH═CCl—, —CH₂CC— or —CF₂— chain then Cy¹is other than a hydrogen atom; or in which

[0096] each Y is a N atom or a CH group, Ar is a3-chloro-5-trifluoromethylpyridin-2-yl group, L¹ is a covalent bond, nis the integer 1 and Alk¹ is a —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂— chain thenCy¹ is other than a hydrogen atom; or in which

[0097] each Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl or2-chloro-6-fluoro-4-trifluoromethylphenyl group, L¹ is a covalent bondand n is zero then Cy¹ is other than a cyclopropyl group; or in which

[0098] each Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl,2-chloro-6-fluoro-4-trifluoromethylphenyl or3-chloro-5-trifluoromethylpyridin-2-yl group, L¹ is a covalent bond andn is zero then Cy¹ is other than a hydrogen atom;

[0099] and with the further proviso that when the compound of formula(1b) is a compound of formula (1d):

[0100] in which:

[0101] L¹ is a covalent bond, n is the integer 1 and Alk¹ is a —CH₂—chain then Ar is other than a 3-methyl-5-trifluoromethylpyridin-2-yl,5-trifluoromethylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl,3,5-difluoropyridin-2-yl, 3,5-dichloropyridin-2-yl or2-chloro-4-trifluoromethylphenyl group.

[0102] Particular compounds of formula (1b) form a further aspect of theinvention and we therefore provide a compound of formula and (1b′):

[0103] wherein:

[0104] the dashed line represents an optional bond;

[0105] A is a —N═ atom or a —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))—group;

[0106] R^(a), R^(b) and R^(c) is each independently a hydrogen atom oran optionally substituted C₁₋₆alkyl group;

[0107] each Y is independently a N atom or CH group or substituted Catom; n is zero or the integer 1;

[0108] Alk¹ is an optionally substituted aliphatic or heteroaliphaticchain L¹ is a covalent bond or a linker atom or group;

[0109] Cy¹ an optionally substituted cycloaliphatic, polycycloaliphatic,heterocycloaliphatic, polyheterocycloaliphatic, aromatic orheteroaromatic group;

[0110] Ar is an optionally substituted aromatic or heteroaromatic group;

[0111] and the salts, solvates, hydrates and N-oxides thereof;

[0112] with the proviso that when the compound of formula (1b″) is acompound of formula (1c):

[0113] in which

[0114] each Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl or2-chloro-6-fluoro-4-trifluoromethylphenyl group, L¹ is a covalent bondand n is zero then Cy¹ is other than a cyclopropyl group.

[0115] It will be appreciated that in the following detailed descriptionof the invention all references to formula (1b) are also references toformulae (1b′) unless specifically stated otherwise.

[0116] It will be further appreciated that compounds of formulae (1a)and (1b) may have one or more chiral centres, and exist as enantiomersor diastereomers. The invention is to be understood to extend to allsuch enantiomers, diastereomers and mixtures thereof, includingracemates. Formulae (1a) and (1b) and the formulae hereinafter areintended to represent all individual isomers and mixtures thereof,unless stated or shown otherwise. In addition, compounds of formulae(1a) and (1b) may exist as tautomers, for example keto (CH₂C═O)-enol(CH═CHOH) tautomers. Formulae (1a) and (1b) and the formulae hereinafterare intended to represent all individual tautomers and mixtures thereof,unless stated otherwise.

[0117] The following general terms as used herein have the statedmeaning unless specifically described otherwise.

[0118] As used herein the term “alkyl” whether present as a group orpart of a group includes straight or branched C₁₋₆alkyl groups, forexample C₁₋₄alkyl groups such as methyl, ethyl, n-propyl, i-propyl,n-butyl, s-butyl, i-butyl or t-butyl groups. Similarly, the terms“alkenyl” or “alkynyl” are intended to mean straight or branchedC₂₋₆alkenyl or C₂₋₆alkynyl groups such as C₂₋₄alkenyl or C₂₋₄alkynylgroups. Optional substituents which may be present on these groupsinclude those optional substituents mentioned hereinafter in relation toAlk¹ when Alk¹ is an optionally substituted aliphatic chain.

[0119] The term halogen is intended to include fluorine, chlorine,bromine or iodine atoms.

[0120] The term “haloalkyl” is intended to include those alkyl groupsjust mentioned sustituted by one, two or three of the halogen atoms justdescribed. Particular examples of such groups include —CF₃, —CCl₃,—CHF₂, —CHCl₂, —CH₂F and —CH₂Cl groups.

[0121] The term “alkoxy” as used herein is intended to include straightor branched C₁₋₆alkoxy e.g. C₁₋₄alkoxy such as methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy and t-butoxy.“Haloalkoxy” as used herein includes any of these alkoxy groupssubstituted by one, two or three halogen atoms as described above.Particular examples include —OCF₃, —OCCl₃, —OCHF₂, —OCHCl₂, —OCH₂F and—OCH₂Cl groups.

[0122] As used herein the term “alkylthio” is intended to includestraight or branched C₁₋₆alkylthio, e.g. C₁₋₄alkylthio such asmethylthio or ethylthio.

[0123] As used herein the term “alkylamino or dialkylamino” is intendedto include the groups —NHR¹ and —N(R¹)₂ [where R¹ is an optionallysubstituted straight or branched alkyl group]. Where two R¹ groups arepresent these may be the same or different. In addition where two R¹groups are present these may be joined together with the N atom to whichthey are attached to form an optionally substituted heterocycloalkylgroup which may contain a further heteroatom or heteroatom containinggroup such as an —O— or —S— atom or —N(R¹)— group. Particular examplesof such optionally substituted heterocycloalkyl groups includeoptionally substituted pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl and N′—C₁₋₆alkyl-piperazinyl groups. The optionalsubstituents which may be present on such heterocycloalkyl groupsinclude those optional substituents as described hereinafter in relationto aliphatic chains.

[0124] When Alk¹ is present in compounds of formulae (1a) and (1b) as anoptionally substituted aliphatic chain it may be an optionallysubstituted C₁₋₁₀aliphatic chain. Particular examples include optionallysubstituted straight or branched chain C₁₋₆alkylene, C₂₋₆alkenylene, orC₂₋₆alkynylene chains.

[0125] Particular examples of aliphatic chains represented by Alk¹include optionally substituted —CH₂—, —CH₂CH₂—, —CH(CH₃)CH₂—,—(CH₂)₂CH₂—, —(CH₂)₃CH₂—, —CH(CH₃)(CH₂)₂CH₂—, —CH₂CH(CH₃)CH₂—,—C(CH₃)₂CH₂—, —CH₂C(CH₃)₂CH₂—, —(CH₂)₂CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—,—CH(CH₃)CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —(CH₂)₂C(CH₃)₂CH₂—,—(CH₂)₄CH₂—, —(CH₂)₅CH₂—, —CHCH—, —CHCHCH₂—, —CH₂CHCH—, —CHCHCH₂CH₂—,—CH₂CHCHCH₂—, —(CH₂)₂CHCH—, —CC—, —CCCH₂—, —CH₂CC—, —CCCH₂CH₂—,—CH₂CCCH₂— or —(CH₂)₂CCH— chains.

[0126] Heteroaliphatic chains represented by Alk¹ in the compounds offormulae (1a) and (1b) include the aliphatic chains just described butwith each additionally containing one, two, three or four heteroatoms orheteroatom-containing groups. Particular heteroatoms or groups includeatoms or groups L² where L² is a linker atom or group. Each L² atom orgroup may interrupt the aliphatic group, or may be positioned at itsterminal carbon atom to connect the group to an adjoining atom or group.Particular examples include optionally substituted -L²CH₂—, —CH₂L²—,-L²CH(CH₃)—, —CH(CH₃)L²—, —CH₂L²CH₂—, -L²CH₂CH₂—, -L²CH₂CH(CH₃)—,—CH(CH₃)CH₂L²—, —CH₂CH₂L²—, —CH₂L²CH₂CH₂—, —CH₂L²CH₂CH₂L²—,—(CH₂)₂L²CH₂—, —(CH₂)₃L²CH₂—, -L²(CH₂)₂CH₂—, -L²CH₂CHCH—, —CHCHCH₂L²—and —(CH₂)₂L²CH₂CH₂— chains.

[0127] When L² is present in heteroaliphatic chains as a linker atom orgroup it may be any divalent linking atom or group. Particular examplesinclude —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—,—S(O)₂—, —N(R²)— [where R² is a hydrogen atom or a straight or branchedalkyl group], —N(R²)O—, —N(R²)N—, —CON(R²)—, —OC(O)N(R²)—, —CSN(R²)—,—N(R²)CO—, —N(R²)C(O)O—, —N(R²)CS—, —S(O)₂N(R²)—, —N(R²)S(O)₂—,—N(R²)CON(R²)—, —N(R²)CSN(R²)— or —N(R²)SO₂N(R²)— groups. Where L²contains two R² groups these may be the same or different.

[0128] The optional substituents which may be present on aliphatic orheteroaliphatic chains represented by Alk¹ include one, two, three ormore substituents where each substituent may be the same or differentand is selected from halogen atoms, e.g. fluorine, chlorine, bromine oriodine atoms, or —OH, —CO₂H, —CO₂R⁴ [where R⁴ is an optionallysubstituted straight or branched C₁₋₆alkyl group], e.g. —CO₂CH₃ or—CO₂C(CH₃)₃, —CONHR⁴, e.g. CONHCH₃, —CON(R⁴)₂, e.g. —CON(CH₃)₂, —COR⁴,e.g. —COCH₃, C₁₋₆alkoxy, e.g. methoxy or ethoxy, haloC₁₋₆alkoxy, e.g.trifluoromethoxy or difluoromethoxy, thiol (—SH), —S(O)R⁴, e.g.—S(O)CH₃, —S(O)₂R⁴, e.g. —S(O)₂CH₃, C₁₋₆alkylthio e.g. methylthio orethylthio, amino, —NHR⁴, e.g. —NHCH₃ or —N(R⁴)₂, e.g. —N(CH₃)₂ groups.Where two R⁴ groups are present in any of the above substituents thesemay be the same or different.

[0129] In addition when two R⁴ alkyl groups are present in any of theoptional substituents just described these groups may be joined,together with the N atom to which they are attached, to form aheterocyclic ring. Such heterocyclic rings may be optionally interruptedby a further heteroatom or heteroatom containing group selected from—O—, —S—, —N(R⁴)—, —C(O)— or —C(S)— groups. Particular examples of suchheterocyclic rings include piperidinyl, pyrazolidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.

[0130] When L¹ is present in compounds of formulae (1a) and (1b) as alinker atom or group it may be any such atom or group as hereinbeforedescribed in relation to L² linker atoms and groups.

[0131] Optionally substituted cycloaliphatic groups represented by thegroup Cy¹ in compounds of the invention include optionally substitutedC₃₋₁₀cycloaliphatic groups. Particular examples include optionallysubstituted C₃₋₁₀cycloalkyl, e.g. C₃₋₇cycloalkyl or C₃₋₁₀cycloalkenyl,e.g C₃₋₇cycloalkenyl groups.

[0132] Optionally substituted heterocycloaliphatic group represented bythe group Cy¹ include optionally substituted C₃₋₁₀heterocycloaliphaticgroup. Particular examples include optionally substitutedC₃₋₁₀heterocycloalkyl, e.g. C₃₋₇heterocycloalkyl orC₃₋₁₀heterocycloalkenyl, e.g. C₃₋₇heterocycloalkenyl groups, each ofsaid groups containing one, two, three or four heteroatoms or heteroatomcontaining groups L⁴ in place of or in addition to the ring carbon atomswhere L⁴ is an atom or group as previously defined for L².

[0133] Optionally substituted polycycloaliphatic groups represented bythe group Cy¹ include optionally substituted C₇₋₁₀bi-or tricycloalkyl orC₇₋₁₀bi- or tricycloalkenyl groups. Optionally substitutedheteropolycycloaliphatic groups represented by the group Cy¹ includeoptionally substituted C₇₋₁₀bi- or tricycloalkyl or C₇₋₁₀bi- ortri-cycloalkenyl groups containing one, two, three, four or more L⁴atoms or groups in place of or in addition to the ring carbon atoms.

[0134] Particular examples of cycloaliphatic, polycycloaliphatic,heterocycloaliphatic and heteropolycycloaliphatic groups represented bythe group Cy¹ include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl,2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl,norbornenyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl,dihydrothiophenyl, tetrahydrothiophenyl, pyrroline, e.g. 2- or3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone,dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl,imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl,5,6-dihydro-2(1H)-pyrazinone, tetrahydropyrimidinyl, thiazolinyl,thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl,homopiperidinyl, heptamethyleneiminyl, piperidinone, 1,4-dioxanyl,morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl,homopiperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl,1,3,5-oxadiazinyl, dihydroisothiazolyl, dihydroisothiazole 1,1-dioxide ,e.g. 2,3-dihydroisothiazole 1,1-dioxide, dihydropyrazinyl andtetrahydropyrazinyl groups.

[0135] The optional substituents which may be present on thecycloaliphatic, polycycloaliphatic, heterocycloaliphatic orheteropolycycloaliphatic groups represented by the group Cy¹ includeone, two, three or more substituents selected from halogen atoms, orC₁₋₆alkyl, e.g. methyl or ethyl, haloC₁₋₆alkyl, e.g. halomethyl orhaloethyl such as difluoromethyl or trifluoromethyl, optionallysubstituted by hydroxyl, e.g. —C(OH)(CF₃)₂, C₁₋₆alkoxy, e.g. methoxy orethoxy, haloC₁₋₆alkoxy, eg. halomethoxy or haloethoxy such asdifluoromethoxy or trifluoromethoxy, thiol, C₁₋₆alkylthiol, e.g.methylthiol or ethylthiol, carbonyl (═O), thiocarbonyl (═S), imino(═NR^(4a)) [where R^(4a) is an —OH group or a C₁₋₆alkyl group], or—(Alk³)_(v)R⁵ groups in which Alk³ is a straight or branchedC₁₋₃alkylene chain, v is zero or the integer 1 and R⁵ is aC₃₋₈cycloalkyl, —OH, —SH, —N(R⁶)(R⁷) [in which R⁶ and R⁷ is eachindependently selected from a hydrogen atom or an optionally substitutedalkyl or C₃₋₈cycloalkyl group], —OR⁶, —SR⁶, —CN, —NO₂, —CO₂R⁶, —SOR⁶,—SO₂R⁶, —SO₃R⁶, —OCO₂R⁶, —C(O)R₂, —OC(O)R⁶, —C(S)R⁶, —C(O)N(R⁶)(R⁷),—OC(O)N(R⁶)(R⁷), —N(R⁶)C(O)R⁷, —C(S)N(R⁶)(R⁷), —N(R⁶)C(S)R⁷,—SO₂N(R⁶)(R⁷), —N(R⁶)SO₂R⁷, —N(R⁶)C(O)N(R⁷)(R⁸) [where R⁸ is as definedfor R⁶], —N(R⁶)C(S)N(R⁷)(R⁸), —N(R⁶)SO₂N(R⁷)(R⁸) or an optionallysubstituted aromatic or heteroaromatic group.

[0136] Particular examples of Alk³ chains include —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH(CH₃)CH₂— chains.

[0137] When R⁵, R⁶, R⁷ and/or R⁸ is present as a C₃₋₈cycloalkyl groupsit may be for example a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl group. Optional substituents which may be present on suchgroups include for example one, two or three substituents which may bethe same or different selected from halogen atoms, for example fluorine,chlorine, bromine or iodine atoms, or hydroxy or C₁₋₆alkoxy, e.g.methoxy, ethoxy or i-propoxy groups.

[0138] When the groups R⁵ and R⁷ or R⁷ and R⁸ are both alkyl groupsthese groups may be joined, together with the N atom to which they areattached, to form a heterocyclic ring. Such heterocyclic rings may beoptionally interrupted by a further heteroatom or heteroatom containinggroup selected from —O—, —S—, —N(R⁷)—, —C(O)— or —C(S)— groups.Particular examples of such heterocyclic rings include piperidinyl,pyrazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,imidazolidinyl and piperazinyl rings.

[0139] When R⁵ is an optionally substituted aromatic or heteroaromaticgroup it may be any such group as described hereinafter in relation toCy¹.

[0140] Additionally, when the group Cy¹ is a heterocycloaliphatic orheteropolycycloaliphatic group containing one or more nitrogen atomseach nitrogen atom may be optionally substituted by a group—(L⁵)_(p)(Alk⁴)_(q)R⁹ in which L⁵ is a —C(O)—, —C(O)O—, —C(S)—, —S(O)₂—,—CON(R⁶)— or —SO₂N(R⁶)—; p is zero or the integer 1; Alk⁴ is anoptionally substituted aliphatic or heteroaliphatic chain; q is zero orthe integer 1; and R⁹ is a hydrogen atom or an optionally substitutedcycloaliphatic, heterocycloaliphatic, polycycloaliphatic,heteropolycycloaliphatic, aromatic or heteroaromatic group as hereindescribed in relation to Cy¹.

[0141] When Alk⁴ is present as an aliphatic or heteroaliphatic chain itmay be for example any aliphatic or heteroaliphatic chain ashereinbefore described for Alk¹.

[0142] Optionally substituted aromatic groups represented by the groupsCy¹ include for example monocyclic or bicyclic fused ring C₆₋₁₂aromaticgroups, such as phenyl, 1- or 2-napthyl, 1- or 2-tetrahydronapthyl,indanyl or indenyl groups.

[0143] Heteroaromatic groups represented by the groups Cy¹ include forexample C₁₋₉heteroaromatic groups containing for example one, two, threeor four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Ingeneral, the heteroaromatic groups may be for example monocyclic orbicyclic fused ring heteroaromatic groups. Monocyclic heteroaromaticgroups include for example five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include forexample eight- to thirteen-membered fused ring heteroaromatic groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms.

[0144] Particular examples of heteroaromatic groups of these typesinclude pyrrolyl, furyl, thienyl, imidazolyl, N-C₁₋₆alkylimidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl,[2,3-dihydro]benzothienyl, benzotriazolyl, indolyl, indolinyl,indazolinyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl,quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo[1,5-a]pyridinyl,imidazo[1,5-a]pyrazinyl, imidazo[1,5-c]pyrimidinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolinyl, isoquinolinyl, phthalazinyl, tetrazolyl,5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, imidyl,e.g. succinimidyl, phthalimidyl or naphthalimidyl such as1,8-naphthalimidyl, pyrazolo[4,3-d]pyrimidinyl, furo[3,2-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl,pyrazolo[3,2-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, thiazolo[3,2-a]pyyridinyl,pyrido[1,2-a]pyrimidinyl, tetrahydroimidazo[1,2-a]pyrimidinyl anddihydroimidazo[1,2-a]pyrimidinyl groups.

[0145] Optional substituents which may be present on aromatic orheteroaromatic groups represented by the group Cy¹ include one, two,three or more substituents, each selected from an atom or group R¹⁰ inwhich R¹⁰ is R^(10a) or -L⁶Alk⁵(R^(10a))_(r), where R^(10a) is a halogenatom, or an amino (—NH₂), substituted amino, nitro, cyano, hydroxyl(—OH), substituted hydroxyl, formyl, carboxyl (—CO₂H), esterifiedcarboxyl, thiol (—SH), substituted thiol, —COR¹¹ [where R¹¹ is an-L⁶Alk³(R^(10a))_(r), aryl or heteroaryl group], —CSR¹¹, —SO₃H, —SOR¹¹,—SO₂R¹¹, —SO₃R¹¹, —SO₂NH₂, —SO₂NHR¹¹, —SO₂N(R¹¹)₂, —CONH₂, —CSNH₂,—CONHR¹¹, —CSNHR¹¹, —CON(R¹¹)₂, —CSN(R¹¹)₂, —N(R¹²)SO₂R¹¹ [where R¹² isa hydrogen atom or a straight or branched alkyl group], —N(SO₂R¹¹)₂,—N(R¹²)SO₂NH₂, —N(R¹²)SO₂NHR¹¹, —N(R¹²)SO₂N(R¹¹)₂, —N(R¹²)COR¹¹,—N(R¹²)CONH₂, —N(R¹²)CONHR¹¹, —N(R¹²)CON(R¹¹)₂, —N(R¹²)CSNH₂,—N(R¹²)CSNHR¹¹, —N(R¹²)CSN(R¹¹)₂, —N(R¹²)CSR¹¹, —N(R¹²)C(O)OR¹¹,—SO₂NHet¹ [where —NHet¹ is an optionally substituted C₅₋₇cyclicaminogroup optionally containing one or more other —O— or —S— atoms or—N(R¹²)—, —C(O)— or —C(S)— groups], —CONHet¹, —CSNHet¹, —N(R¹²)SO₂NHet¹,—N(R¹²)CONHet¹, —N(R¹²)CSNHet¹, —SO₂N(R¹²)Het [where -Het is anoptionally substituted monocyclic C₅₋₇carbocyclic group optionallycontaining one or more other —O— or —S— atoms or —N(R¹²)—, —C(O)—,—S(O)— or —S(O)₂— groups], -Het, —CON(R¹²)Het, —CSN(R¹²)Het,—N(R¹²)CON(R¹²)Het, —N(R¹²)CSN(R¹²)Het, N(R¹²)SO₂N(R¹²)Het, aryl orheteroaryl groups; L⁶ is a covalent bond or a linker atom or group ashereinbefore defined for L²; Alk⁵ is an optionally substituted straightor branched C₁₋₆alkylene, C₂₋₆alkenylene or C₂₋₆alkynylene chain,optionally interrupted by one, two or three —O— or —S— atoms or—S(O)_(n)— [where n is an integer 1 or 2] or —N(R¹²)— e.g. —N(CH₃)—groups; and r is zero or the integer 1, 2, or 3. It will be appreciatedthat when two R¹¹ or R¹² groups are present in one of the abovesubstituents the R¹¹ and R¹² groups may be the same or different.

[0146] When in the group -L⁶Alk⁵(R^(10a))_(r) r is an integer 1, 2 or 3,it is to be understood that the substituent or substituents R^(10a) maybe present on any suitable carbon atom in -Alk⁵. Where more than oneR^(10a) substituent is present these may be the same or different andmay be present on the same or different atom in -Alk⁵. Clearly, when ris zero and no substituent R^(10a) is present the alkylene, alkenyleneor alkynylene chain represented by Alk⁵ becomes an alkyl, alkenyl oralkynyl group.

[0147] When R^(10a) is a substituted amino group it may be for example agroup —NHR¹¹ [where R¹¹ is as defined above] or a group —N(R¹¹)₂ whereineach R¹¹ group is the same or different.

[0148] When R^(10a) is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

[0149] When R^(10a) is a substituted hydroxyl or substituted thiol groupit may be for example a group —OR¹¹ or a —SR¹² group respectively.

[0150] Esterified carboxyl groups represented by the group R^(10a)include groups of formula —CO₂Alk⁶ wherein Alk⁶ is a straight orbranched, optionally substituted C₁₋₈alkyl group such as a methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; aCO₁₂arylC₁₋₈alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxypropyl group. Optional substituents presenton the Alk⁶ group include R^(10a) atoms and groups as described above.

[0151] When Alk⁵ is present in or as a substituent it may be for examplea —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—,CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—, —C(CH₃)₂CH₂—, —CH═CH—,—CH═CCH₂—, —CH₂C═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH₂—,—CC—, —CCCH₂—, —CH₂CC—, —CCCH₂CH₂—, —CH₂CCCH₂— or —CH₂CH₂CC— chain,optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O)₂— or —N(R¹²)—, e.g. —N(CH₃)— groups. The aliphatic chainsrepresented by Alk⁵ may be optionally substituted by one, two or threehalogen atoms in addition to any R^(10a) groups that may be present.

[0152] Aryl or heteroaryl groups represented by the groups R^(10a) orR¹¹ include mono- or bicyclic optionally substituted C₆₋₁₂ aromatic orC₁₋₉ heteroaromatic groups as described above for the group Cy¹. Thearomatic and heteroaromatic groups may be attached to the group Cy¹ incompounds of formula (1) by any carbon or hetero e.g. nitrogen atom asappropriate.

[0153] It will be appreciated that when —NHet¹ or -Het forms part of asubstituent R¹⁰ the heteroatoms or heteroatom containing groups that maybe present within the ring —NHet¹ or -Het take the place of carbon atomswithin the parent carbocyclic ring.

[0154] Thus when —NHet¹ or -Het forms part of a substituent R¹⁰ each maybe for example an optionally substituted pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl orthiazolidinyl group. Additionally Het may represent for example, anoptionally substituted cyclopentyl or cyclohexyl group. Optionalsubstituents which may be present on —NHet¹ include those substituentsdescribed above when Cy¹ is a heterocycloaliphatic group.

[0155] Particularly useful atoms or groups represented by R¹⁰ includefluorine, chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl,ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substitutedphenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, or thienyl,C₁₋₆hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC₁₋₆alkyl,e.g. carboxyethyl, C₁₋₆alkylthio e.g. methylthio or ethylthio,carboxyC₁₋₆alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or3-carboxy-propylthio, C₁₋₆alkoxy, e.g. methoxy or ethoxy,hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy,pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C₃₋₇cycloalkyl, e.g.cyclobutyl, cyclopentyl, C₅₋₇cycloalkoxy, e.g. cyclopentyloxy,haloC₁₋₆alkyl, e.g. trifluoromethyl, haloC₁₋₆alkoxy, e.g.trifluoromethoxy, C₁₋₆alkylamino, e.g. methylamino, ethylamino,—CH(CH₃)NH₂ or —C(CH₃)₂NH₂, haloC₁₋₆alkylamino, e.g.fluoroC₁₋₆alkylamino, e.g. —CH(CF₃)NH₂ or —C(CF₃)₂NH₂, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g.ethylaminoethyl, C₁₋₆dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl,aminoC₁₋₆alkoxy, e.g. aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g.methylaminoethoxy, C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g. dimethylaminoethoxy,diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy,imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido,nitro, cyano, hydroxyl (—OH), formyl [HC(O)—], carboxyl (—CO₂H),—CO₂Alk⁶ [where Alk⁶ is as defined above], C₁₋₆ alkanoyl e.g. acetyl,optionally substituted benzoyl, thiol (—SH), thioC₁₋₆alkyl, e.g.thiomethyl or thioethyl, sulphonyl (—SO₃H), C₁₋₆alkylsulphonyl, e.g.methylsulphonyl, aminosulphonyl (—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g.methylaminosulphonyl or ethylaminosulphonyl, C₁₋₆dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g.methylaminocarbonyl or ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl,e.g. dimethylaminocarbonyl or diethylaminocarbonyl,aminoC₁₋₆alkylaminocarbonyl, e.g. aminoethylamino-carbonyl,C₁₋₆dialkylaminoC₁₋₆alkylaminocarbonyl, e.g.diethylaminoethyl-aminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylamino-carbonylamino, e.g.dimethylaminocarbonylamino or diethylamino-carbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethylamino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonyl-amino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, —CONHC(═NH)NH₂,C₁₋₆alkylsulphonyl-amino, e.g. methylsulphonylamino orethylsulphonylamino, C₁₋₅dialkyl-sulphonylamino, e.g.dimethylsulphonylamino or diethylsulphonylamino, optionally substitutedphenylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂),C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g.dimethyl-aminosulphonylamino or diethylaminosulphonylamino, optionallysubstituted morpholinesulphonylamino ormorpholinesulphonylC₁₋₆alkylamino, optionally substitutedphenylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylaminoC₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino or optionally substituted benzyloxy,pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino,benzyloxycarbonylaminoC₁₋₆alkyl e.g. benzyloxycarbonylaminoethyl,benzothio, pyridylmethylthio or thiazolylmethylthio groups.

[0156] A further particularly useful group of substituents representedby R¹⁰ when present on aromatic or heteroaromatic groups includessubstituents of formula -L⁶Alk⁵R^(10a) where L⁶ is preferably a covalentbond or an —O— or —S— atom or —N(R²)—, —C(O)—, —C(O)O—, —O—C(O)—,—N(R²)CO—, —CON(R²)— or —N(R²)S(O)₂— group, Alk⁵ is an optionallysubstituted C₁₋₆-alkyl group optionally interrupted by one or two —O— or—S— atoms or —N(R¹²)—, —C(O)—, —C(S)—, —CON(R¹²)— or —N(R¹²)CO— groupsand R^(10a) is an optionally substituted Het group as herein defined oran optionally substituted heteroaromatic group as hereinbefore describedin relation to Cy¹.

[0157] Where desired, two R¹⁰ substituents may be linked together toform a cyclic group such as a cyclic ether, e.g. a C₁₋₆alkylenedioxygroup such as methylenedioxy or ethylenedioxy.

[0158] It will be appreciated that where two or more R¹⁰ substituentsare present, these need not necessarily be the same atoms and/or groups.In general, the substituent(s) may be present at any available ringposition on the aromatic or heteroaromatic group represented by thegroup Cy¹.

[0159] When in compounds of formula (1a) X is a substituted —N— atom orin compounds of formulae (1a) or (1b) Y is a substituted C atom thesubstituents which may be present on the N or C atom include those R¹⁰atoms and groups as hereinbefore defined.

[0160] When Ar is present in compounds of formulae (1a) or (1b) as anoptionally substituted aromatic or heteroaromatic group it may be anysuch group as hereinbefore described for Cy¹. Optional substituentswhich may be present include those R¹⁰ atoms and groups as described inrelation to Cy¹ aromatic and heteroaromatic groups.

[0161] One useful group of compounds according to the invention is thatwhere Y is a CH group or a substituted C atom where the substituent onthe C atom may in general be any R¹⁰ atom or group as hereinbeforedescribed or in particular a R²⁰ group as hereinafter defined.

[0162] A particularly useful group of compounds according to theinvention is represented by the compounds of formula (1a).

[0163] An especially useful group of compounds according to theinvention has the formula (2a):

[0164] in which

[0165] R²⁰ is a hydrogen atom or an atom or group R¹⁰ as hereinbeforedefined;

[0166] the dashed line, A, R^(a), Alk¹, n, L¹, Cy¹, X and Ar are asgenerally and specifically defined previously;

[0167] and the salts, solvates, hydrates and N-oxides thereof.

[0168] In general in compounds of formula (1a), (1b) and (2a) R^(a) ispreferably a hydrogen atom or a C₁₋₄alkyl group, especially a methyl,ethyl, n-propyl or i-propyl group. Most preferably R^(a) is a methylgroup or most especially a hydrogen atom.

[0169] In one particularly preferred class of compounds of formula (1a),(1b) and (2a) the dashed line represents a bond and A is a —C(R^(b))═group. In this class of compounds R^(b) is preferably a C₁₋₄alkyl group,especially a methyl, ethyl, n-propyl or i-propyl group. Most preferablyR^(b) is a methyl group or most especially a hydrogen atom.

[0170] In one preferred class of compounds of formulae (1a) and (2a) Xis a —O— or —S— atom, most preferably a —S— atom.

[0171] In another preferred group of compounds of formulae (1a), (1b)and (2a) n is zero.

[0172] In another preferred group of compounds of formulae (1a), (1b)and (2a) n is the integer 1 and Alk¹ is preferably an optionallysubstituted C₁₋₆alkylene chain, especially an optionally substituted—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂— or —CH₂CH(CH₃)— chain, mostespecially a —CH₂— or —CH₂CH₂— chain.

[0173] In compounds of formula (2a) and in general in compounds of theinvention L¹ is preferably a covalent bond or an —O— or —S— atom or an—N(R²)—, especially —NH— or —N(CH₃)—, —C(O)—, —C(S)—, —S(O)— or —S(O)₂—group. Most preferably L¹ is a covalent bond or an —O— or —S— atom or—NH— group. L¹ is most especially preferably is a covalent bond.

[0174] In compounds of formula (2a) and in general in compounds of theinvention Cy¹ is preferably an optionally substituted cycloaliphatic,aromatic or heteroaromatic group as hereinbefore generally andparticularly defined.

[0175] Particularly preferred Cy¹ optionally substituted cycloaliphaticgroups include optionally substituted C₃₋₇cycloalkyl groups, especiallycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups.

[0176] Particularly preferred optional substituents which may be presenton Cy¹ optionally substituted cycloaliphatic groups include halogenatoms, especially fluorine, chlorine or bromine atoms, or C₁₋₆alkylgroups, especially C₁₋₃alkyl groups, most especially a methyl group, ora haloC₁₋₆alkyl group, especially a fluoroC₁₋₆alkyl group, mostespecially a —CF₃ group, or a C₁₋₆alkoxy, especially methoxy, ethoxy,propxy or i-propoxy group, or a haloC₁₋₆alkoxy, especially afluoroC₁₋₆alkoxy, most especially a —OCF₃ group, or a cyano (—CN),esterified carboxyl, especially —CO₂CH₃ or —O₂C(CH₃)₃, nitro (—NO₂),amino (—NH₂), substituted amino, especially —NHCH₃ or —N(CH₃)₂, —C(O)R⁶,especially —C(O)CH₃, or —N(R⁶)C(O)R⁷, especially —NHCOCH₃ group.

[0177] Particularly preferred Cy¹ aromatic groups include optionallysubstituted phenyl groups. Particularly preferred heteroaromatic groupsinclude optionally substituted monocyclic heteroaromatic groups,especially optionally substituted five- or six-membered heteroaromaticgroups containing one, two, three or four heteroatoms selected fromoxygen, sulphur or nitrogen atoms. Particularly preferred optionallysubstituted monocyclic heteroaromatic groups include optionallysubstituted furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl,pyrimidinyl or triazinyl group.

[0178] Particularly preferred optional substituents which may be presenton Cy¹ aromatic or heteroaromatic groups include atoms or groups—R^(10a) or -L⁶Alk⁵(R^(10a))_(r) as hereinbefore defined. Particularlyuseful optional substituents include halogen atoms, especially fluorine,chlorine or bromine atoms, or C₁₋₆alkyl groups, especially C₁₋₃alkylgroups, most especially a methyl group, or a haloC₁₋₆alkyl group,especially a fluoroC₁₋₆alkyl group, most especially a —CF₃ group, or aC₁₋₆alkoxy, especially methoxy, ethoxy, propxy or i-propoxy group, or ahaloC₁₋₆alkoxy, especially a fluoroC₁₋₆alkoxy, most especially a —OCF₃group, or a cyano (—CN), carboxyl (—CO₂H), esterified carboxyl(—CO₂Alk⁶), especially —CO₂CH₃, —CO₂CH₂CH₃, or —CO₂C(CH₃)₃, nitro(—NO₂), amino (—NH₂), substituted amino, especially —NHCH₃ or —N(CH₃)₂,—COR¹¹, especially —COCH₃, or —N(R¹²)COR¹¹, especially —NHCOCH₃ group.

[0179] Further preferred optional substituents which may be present onCy¹ aromatic or heteroaromatic groups include groups of formula-L⁶Alk⁵(R^(10a))_(r) in which r is the integer 1, L⁶ is a covalent bondor an —O— or —S— atom or a —N(R²)—, especially —NH— or —N(CH₃)—, —C(O)—,—C(S)—, —C(O)O—, —OC(O)—, —N(R²)CO—, especially —NHCO—, or —CON(R²)—,especially —CHNH-group, Alk⁵ is a C₁₋₆alkyl chain, especially a —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂— chain and R^(10a) is asubstituted hydroxyl group, especially a —OCH₃, —OCH₂CH₃ or —OCH(CH₃)₂group or a substituted amino group, especially a —N(CH₃)₂ or —N(CH₂CH₃)₂group or a -Het group, especially an optionally substituted monocyclicC₅₋₇carbocyclic group containing one, two or three —O—, —S—, —N(R¹²)—,especially —NH— or —N(CH₃)— or —C(O)— groups within the ring structureas previously described, most especially an optionally substitutedpyrrolidinyl, imidazolidinyl, piperidinyl, e.g. N-methylpiperidinyl,morpholinyl, thiomorpholinyl or piperazinyl group or R^(10a) is anoptionally substituted heteroaromatic group, especially a five- orsix-membered monocyclic heteroaromatic group containing one, two, threeor four heteroatoms selected from oxygen, sulphur or nitrogen atoms,such as optionally substituted pyrrolyl, furyl, thienyl, imidazolyl,triazolyl, pyridyl, pyrimidinyl, triazinyl, pyridazinyl, or pyrazinylgroup. Particularly preferred optional substituents on the -Het groupsjust described include hydroxyl (—OH) and carboxyl (—CO₂H) groups orthose preferred optional substituents just described in relation to thegroup Cy¹.

[0180] In one preferred class of compounds of formula (2a) R²⁰ is anatom or group —R^(10a) or L⁶Alk⁶(R^(10a))_(r) as hereinbefore defined.Preferably R²⁰ is a preferred atom or group as just defined for Cy¹. Inone particularly preferred class of compounds of formula (2a) R²⁰ is ahydrogen atom or a carboxyl (—CO₂H), esterified carboxyl (—CO₂Alk⁶),especially —CO₂CH₃, —CO₂CH₂CH₃, or —CO₂C(CH₃)₃, —CN, —NH₂, —CONH₂,—CONHR¹¹, —N(R¹²)SO₂R¹¹, —N(R¹²)C(O)OR¹¹ or —O₂R¹¹ group.

[0181] In one particularly preferred group of compounds of formula (1),(1a) and (2a) Cy¹ is an optionally substituted phenyl group, especiallya phenyl group optionally substituted by one, two or three optionalsubstituents where at least one, and preferably two optionalsubstituents are located ortho to the bond joining Cy¹ to the remainderof the compound of formula (1), (1a) or (2a). Particularly preferredortho substituents include halogen atoms, especially fluorine orchlorine atoms, or C₁₋₃alkyl groups, especially methyl groups,C₁₋₃alkoxy groups, especially methoxy, haloC₁₋₃alkyl groups, especially—CF₃, haloC₁₋₃alkoxy groups, especially —OCF₃, or cyano (—CN), groups.In this class of compounds a second or third optional substituent whenpresent in a position other than the ortho positions of the ring Cy¹ maybe preferably an atom or group —R^(10a) or -L⁶Alk⁵(R^(10a))_(r) asherein generally and particularly described.

[0182] Particularly preferred Ar aromatic groups include optionallysubstituted phenyl groups. Particularly preferred heteroaromatic groupsinclude optionally substituted monocyclic heteroaromatic groups,especially optionally substituted five- or six-membered heteroaromaticgroups containing one, two, three or four heteroatoms selected fromoxygen, sulphur or nitrogen atoms. Particularly preferred optionallysubstituted monocyclic heteroaromatic groups include optionallysubstituted furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl,pyrimidinyl or triazinyl group.

[0183] Particularly preferred optional substituents which may be presenton Ar aromatic or heteroaromatic groups include atoms or groups —R^(10a)or -L⁶Alk⁵(R^(10a))_(r) as hereinbefore defined. Particularly usefuloptional substituents include halogen atoms, especially fluorine,chlorine or bromine atoms, or C₁₋₆alkyl groups, especially C₁₋₃alkylgroups, most especially a methyl group, or a haloC₁₋₆alkyl group,especially a fluoroC₁₋₆alkyl group, most especially a —CF₃ group, or aC₁₋₆alkoxy, especially methoxy, ethoxy, propxy or i-propoxy group, or ahaloC₁₋₆alkoxy, especially a fluoroC₁₋₆alkoxy, most especially a —OCF₃group, or a cyano (—CN), esterified carboxyl, especially —CO₂CH₃ or—CO₂C(CH₃)₃, nitro (—NO₂), amino (—NH₂), substituted amino, especially—NHCH₃ or —N(CH₃)₂, —COR¹¹, especially —COCH₃, or —N(R¹²)COR¹¹,especially —NHCOCH₃ group.

[0184] In one particularly preferred class of compounds of formula (2a)the dashed line is present, A is a —CH═ group, R^(a) is a hydrogen atomand X is a —S— atom.

[0185] A further particularly useful class of compounds according to theinvention has the formula (1b) in which the dashed line is present, A isa —CH═ group, R^(a), Ar, Alk¹, n and L¹ are as defined for formula (1b),each Y is independently a CH group or substituted C atom and Cy¹ is anoptionally substituted aromatic or heteroaromatic group

[0186] Particularly useful compounds of the invention include:

[0187] Ethyl6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0188] Ethyl 7-cyclopropylmethyl-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0189] Ethyl6-oxo-3-phenyl-7-(3-thienyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0190] Ethyl3-(4-fluorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0191] Ethyl3-(2-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0192] Ethyl6-oxo-7-phenyl-3-(4-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0193] Ethyl3-(3-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0194]6-Oxo-3,7-diphenyl-N-(2-piperidinoethyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;

[0195]6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile;

[0196] 3,7-Diphenylthieno[2,3-b]pyridin-6(7H)-one;

[0197] Ethyl3-(2,4-difluorophenyl)-7-[4-(4-methylpiperazin-1-yl)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0198] 1,4-Diphenyl-1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one;

[0199] Ethyl7-(2-chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;

[0200] and the salts, solvates, hydrates and N-oxides thereof.

[0201] The compounds of the invention may be prepared by a number ofprocesses as generally described below and more specifically in theExamples hereinafter. In the following process description, the symbolsAr, Cy¹, Alk¹, n, L¹, R^(a), R^(b), R^(c), A, X and Y when used in theformulae depicted are to be understood to represent those groupsdescribed above in relation to formulae (1a) and (1b) unless otherwiseindicated. In the reactions described below, it may be necessary toprotect reactive functional groups, for example hydroxy, amino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice [see, forexample, Green, T. W. in “Protective Groups in Organic Synthesis”, JohnWiley and Sons, 1999]. In some instances, deprotection may be the finalstep in the synthesis of a compound of formula (1) and the processesaccording to the invention described hereinafter are to be understood toextend to such removal of protecting groups. For convenience theprocesses described below all refer to a preparation of a compound offormula (1a) or (1b) but clearly the description applies equally to thepreparation of compounds of formula (2a).

[0202] Thus according to a further aspect of the invention a compound offormula (1a) in which Y is a substituted e.g. —CO₂CH₂CH₃ substituted Catom may be prepared according to the reactions set out in Scheme 1:

[0203] Thus a compound of formula (1a) in which Y is a substituted Catom may be prepared by reaction of a compound of formula (7) with analkylating agent of formula Cy¹L¹(Alk¹)_(n)Z, where Z is a leaving groupsuch as a halogen atom, e.g. a chlorine, bromine or iodine atom or asulphonyloxy group such as an alkylsulphonyloxy e.g.trifluoromethylsulphonyloxy or arylsulphonyloxy e.g. phenylsulphonyloxygroup.

[0204] The reaction may be performed in the presence of a solvent, forexample a substituted amide such as dimethylformamide, optionally in thepresence of a base, for example an inorganic base such as sodiumhydride, or an organic base such as an organic amine, e.g. a cyclicamine such as 1,5-diazabicyclo[4.3.0]non-5-ene or a resin bound organicamine such as resin bound2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(PS-BEMP), at an elevated temperature, for example 80 to 100° C.

[0205] In a further aspect of the invention a compound of formula (1a)in which, for example, L¹ is a covalent bond and n is zero may beprepared by the reaction of a compound of formula (7) with a boronicacid of formula Cy¹B(OH)₂. The reaction may be performed in an organicsolvent, for example a halogenated hydrocarbon such as dichloromethaneor dichloroethane in the presence of a copper reagent, for example acopper (II) reagent such as copper (II) acetate, optionally in thepresence of an oxidant, for example 2,2,6,6-tetramethyl-1-piperidinyloxyor pyridine-N-oxide, optionally in the presence of a base, for examplean organic amine such as an alkylamine, e.g. triethylamine or anaromatic amine, e.g. pyridine at a temperature from around ambient tothe reflux temperature [see for example Chan, D. T. et al TetrahedronLetters, 1998, 2933; Lam, P.Y.S. et al, Tetrahedron Letters, 2001, 3415]

[0206] Clearly the reactions just described may be used to prepare othercompounds of the invention starting from intermediates of formula (7a)or (7b):

[0207] for instance compounds of formula (7a) in which Y is a CH group.

[0208] Intermediates pyridinones of formula (7) may be prepared frompyridine N-oxides of formula (6) by sequential reaction with ananhydride, for example acetic anhydride at an elevated temperature, forexample the reflux temperature followed by reaction with an inorganicbase, for example a carbonate such as aqueous potassium carbonate in asolvent such as an ether for example a cyclic ether e.g. tetrahydrofuranat around ambient temperature.

[0209] Pyridine N-oxides of formula (6) may be formed from pyridines offormula (5) by standard methods of formation of N-oxides as describedhereinafter.

[0210] Pyridines of formula (5) may be formed from2-halopyridyl-(hetero)arylmethanones of formula (4) by reaction with areagent of formula HXCH₂CO₂R³⁰ [where R³⁰ is a C₁₋₆alkyl group such as amethyl or ethyl group]. The reaction may be performed in the presence ofa solvent such as a substituted amide for example dimethylformamide oran ether e.g. a cyclic ether such as tetrahydrofuran in the presence ofa base, for example an inorganic base such as a hydride e.g. sodiumhydride or an organic base such as 1,5-diazabicyclo[4.3.0]non-5-ene or atrialkylamine such as triethylamine at a temperature between about 0° C.and ambient temperature.

[0211] 2-Halopyridyl-(hetero)arylmethanones of formula (4) may beprepared from 2-halopyridines of formula (3) by reaction with a base,for example a strong base such as lithium diisopropylamide or butyllithium to form a 2-halopyridyl anion and quenching with a (hetero)arylamide such as a Weinreb amide. The reaction may be performed in thepresence of a solvent such as a substituted amide for exampledimethylformamide or an ether e.g. a cyclic ether such as, at atemperature of around −78° C.

[0212] According to another aspect of the invention further compounds offormula (1a) may be prepared according to the reactions set out inScheme 2.

[0213] Thus further compounds of formula (1a) may be prepared fromintermediates of formula (13), and intermediates of formula (14) may beprepared from intermediates of formula (12), by functionalisation at the6-membered ring nitrogen according to the methods as previouslydescribed for the conversion of compounds of formula (7) to compounds offormula (1a).

[0214] Further compounds of formula (1a) may also be prepared fromhalogen substituted e.g. bromine substituted intermediates of formula(14), and intermediates of formula (13) may be prepared from halogensubstituted e.g. bromine substituted intermediates of formula (12) byreaction with a boronic acid of formula ArB(OH)₂. The reaction may beperformed in a solvent such as an acyclic ether, for example ethyleneglycol dimethyl ether or a cyclic ether, for example tetrahydrofuran oran aromatic hydrocarbon, for example toluene in the presence of aninorganic catalyst such as a palladium catalyst e.g.tetrakis(triphenylphosphine) palladium (0) in the presence of a base,for example an aqueous inorganic base such as aqueous sodium, potassiumor caesium carbonate at an elevated temperature, for example around 80°C.

[0215] Pyridinones of formula (12) and pyridine N-oxides of formula (11)may be prepared by the methods as hereinbefore described.

[0216] Halides, for example bromides, of formula (10) may be prepared bysuch well known methods as for example the Sandmeyer reaction. Thus forexample a bromide of formula (10) may be prepared by treatment of anaryl amine of formula (9) with an alkyl nitrite, for example t-butylnitrite and a copper salt, for example copper (II) bromide in thepresence of a solvent, for example a nitrile such as acetonitrile at atemperature from about 0° to around 65° C.

[0217] Aryl amines of formula (9) may be prepared from halo nitrites offormula (8) by analogous methods to those used to prepare compounds offormula (5) as herein described.

[0218] Further 5-6 fused ring bicyclic heteroaromatic intermediates offormulae (15) and (17) may be prepared from intermediates of formula (4)by the methods shown in Scheme 3.

[0219] Thus pyrazolo[3,4-b]pyridines of formula (15) may be prepared byreaction of a 2-halopyridyl (or 2-halopyrimidinyl)-(hetero)arylmethanoneof formula (4) with an optionally substituted hydrazine of formulaR¹⁰NHNH₂. The reaction may be performed in a solvent such as an amidefor example a substituted amide e.g. dimethylformamide, at an elevatedtemperature, for example from about 60° C. to the reflux temperature.

[0220] Similarly intermediate isoxazolo[3,4-b]pyridines of formula (17)may be prepared by reaction of a 2-halopyridyl (or2-halopyrimidinyl)-(hetero)arylmethanone of formula (4) withhydroxylamine in the presence of an proton source for example hydrogenchloride in a solvent such as an alcohol, e.g. methanol or ethanol at atemperature from ambient to the reflux temperature to give anintermediate of formula (16) which may be cyclised to an intermediate offormula (17) by reaction with a base, for example an organic base suchas 1,5-diazabicyclo[4.3.0]non-5-ene (DBU) or an inorganic base such as ahydride e.g. sodium hydride in a solvent such as an amide for example asubstituted amide e.g. dimethylformamide or an ether such as a cyclicether e.g. tetrahydrofuran at a temperature from about 0° C. to ambienttemperature.

[0221] Further pyrrolo[3,2-b]pyrimidine intermediates of formula (20)may be prepared from intermediates of formula (18) by the methods shownin Scheme 4.

[0222] Thus a 1H-pyrrolo[3,2-b]pyridine (A═CH) or1H-pyrrolo[3,2-b]pyrimidine (A═N) of formula (19) may be converted to anintermediate of formula (20) by reaction with a compound of formula Ar-L(in which L is a leaving group such as a halogen atom e.g. a fluorine,chlorine, bromine or iodine atom or a aryl sulfonate such as atriflate). The reaction may be performed in the presence of a base, forexample a hydride such as sodium hydride or a carbonate such aspotassium or caesium carbonate, in a solvent such as a sulfoxide e.g.dimethyl sulfoxide or an amide e.g. dimethylacetamide ordimethylformamide, at an elevated temperature e.g. from about ₆₀° C. to120° C. [according to the methods of Glamkowski, E. J. et al, J. Med.Chem., 1985, 28, 66 and Stabler, S. R. et al, Synth. Commun., 1994, 24,123-29]. Alternatively the reaction may be performed with a compound offormula Ar-L (in which L is a leaving group such as a halogen atom e.g.a bromine atom or a aryl sulfonate such as a triflate) in the presenceof a catalyst such as a copper catalyst e.g. copper (I) bromide in thepresence of an inorganic base such as a carbonate e.g. potassium orcaesium carbonate in a solvent such as an aromatic amine e.g. pyridine[according to the method of Ishii, H. et al, J. Chem. Soc. Perkin Trans.1, 1989, 2407]. Alternatively the reaction may be performed with acompound of formula Ar-L (in which L is a leaving group such as ahalogen atom e.g. a bromine atom or a aryl sulfonate such as a triflate)in the presence of a catalyst such as a palladium catalyst e.g.palladium (ii) acetate in the presence of an iron catalyst e.g.1,1′-bis(diphenylphosphino)ferrocene in a solvent such as an aromatichydrocarbon e.g. toluene at an elevated temperature e.g. between 80° C.and the reflux temperature [according to the method of Mann, G. et al,J. Am. Chem. Soc., 1998, 120, 827-8].

[0223] Intermediates of formula (19) may be formed from nitropyridines(A═CH) or nitropyrimidines (A═N) of formula (18) by sequential reactionwith a dialkoxymethyl-dimethyl-amine such asdimethoxymethyl-dimethyl-amine followed by catalytic reduction with apalladium catalyst such as palladium on carbon [according to the methodof Mahadevan, I. et al, J. Heterocyclic Chem., 1992,29, 359-67].

[0224] Further 5-6 fused ring bicyclic heteroaromatic intermediates foruse in the preparation of compounds of formula (1a) and (1b) may beprepared according to the methods of Japanese Patent ApplicationJP9059276.

[0225] Such 5-6 fused ring bicyclic heteroaromatic intermediates offormula (15), (17), (19) and (20) as just described may be convertedinto further compounds of the invention by the particular methods asdescribed above and general methods described below.

[0226] Further compounds of the invention in which A is a —N═ atom maybe prepared according to the methods shown in Scheme 5.

[0227] Thus an intermediate of formula (25) may be converted to acompound of the invention according to the methods as herein describedfor the conversion of compounds of formula (7) to compounds of formula(1a).

[0228] Intermediates of formula (25) may be prepared from intermediatesof formula (24) by cleavage of an ether group. Thus when R³¹ is a benzylgroup it may be cleaved by such well known methods as catalyticreduction with hydrogen gas in the presence of a catalyst such as apalladium catalyst e.g. palladium on charcoal. When R³¹ is an alkylether, e.g. a methyl ether it may be cleaved by reaction with atrialkylsilyl halide such as trimethylsilyl chloride, optionally in thepresence of an inorganic halide such as sodium iodide in a solvent suchas a halogenated hydrocarbon e.g. dichloromethane or in a nitrile e.g.acetonitrile [according to the methods of Kundu, N. G. et al, J. Chem.Soc. Perkin Trans. I, 1990, 1822].

[0229] Intermediates of formula (25) may also be prepared fromintermediates of formula (23) sequential by base hydrolysis, for examplesoudium or potassium hydroxide hydrolysis in a solvent such as analcohol, e.g. methanol or ethanol at an elevated temperature, e.g. thereflux temperture, followed by re-esterification by reaction with anacidified alcohol, e.g hydrogen chloride saturated ethanol at anelevated temperature, e.g. the reflux temperature.

[0230] Intermediates of formula (24) may be prepared from intermediatesof formula (23) by reaction with an alkoxide, e.g. sodium methoxide orsodium benzyloxide in a solvent such as an alcohol, e.g. methanol orethanol at a temperture between about 0° C. and the reflux temperature.Alternatively the reaction may be performed with an alcohol, e.g.methanol or benzyl alcohol in the presence of a strong base, e.g. ahydride such as sodium hydride in an inert solvent such as an amide,e.g. dimethylformamide at a temperature between about 0° C. and 80° C.

[0231] Intermediates of formula (23) may be formed from intermediates offormula (22) in a similar manner to that described for the preparationof intermediates of formula (5) form intermediates of formula (4).

[0232] Intermediates of formula (22) may be formed from intermediates offormula (21) by reaction with a strong base, e.g. lithiumtetramethylpiperidine (LiTMP) in a solvent or mixture of solvents, forexample an ether such as diethyl ether of tetrahydrofuran or a mixturethereof at a low temperature, e.g. around −100° C. to form a lithiumanion [according to the methods of Queguiner et al, J. Het. Chem. 1990,27, 1377 and Mattson et al, J. Org. Chem. 1990, 55, 3410] which may befurther reacted with a Weinreb amide at a temperature from about −78° C.to ambient temperature.

[0233] As an alternative a lithium anion as just described may bereacted with an aldehyde of formula ARCHO under the reaction conditionsjust described to give an intermediate alcohol which may be oxidisedgive an intermediate of formula (22) by such well known methods asmanganese dioxide in a solvent, e.g. a halogenated hydrocarbon such asdichloromethane.

[0234] Compounds of the invention and intermediates thereto where Arepresents a —N(R^(b))— or —C(R^(b))(R^(c))— group may be generated fromcompounds of the invention or intermediates thereto where A represents a—N═ or —C(R^(b))═ group by reduction, for instance by catalytichydrogenation using a metal catalyst such as palladium on charcoal inthe presence of hydrogen gas at an elevated pressure in a solvent suchas an alcohol, e.g. ethanol optionally at an elevated temperaure e.g.between 40 and 60°.

[0235] Where in the general processes described above intermediates suchas alkylating agents of formula Cy¹L¹(Alk¹)_(n)Z, amides of formulaArC(O)N(OMe)Me, reagents of formula HXCH₂CO2Et and nitroaromatics offormula (18) and any other intermediates required in the synthesis ofcompounds of the invention are not available commercially or known inthe literature, they may be readily obtained from simpler knowncompounds by one or more standard synthetic methods employingsubstitution, oxidation, reduction or cleavage reactions. Particularsubstitution approaches include conventional alkylation, arylation,heteroarylation, acylation, thioacylation, halogenation, sulphonylation,nitration, formylation and coupling procedures. It will be appreciatedthat these methods may also be used to obtain or modify otherintermediates and in particular compounds of formulae (1a) and (1b)where appropriate functional groups exist in these compounds. Particularexamples of such methods are given in the Examples hereinafter.

[0236] Thus for example aromatic halogen substituents in the compoundsmay be subjected to halogen-metal exchange with a base, for example alithium base such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuranand then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing dimethylformamide as the electrophile, a thiomethyl group may beintroduced by using dimethyidisulphide as the electrophile, an alcoholgroup may be introduced by using an aldehyde as electrophile and an acidmay be introduced by using carbon dioxide as electrophile. Aromaticacids of formula ArCO₂H may also be generated by quenching Grignardreagents of formula ArMgHal with carbon dioxide.

[0237] Aromatic acids of formula ArCO₂H generated by this method andacid containing compounds in general may be converted to activatedderivatives, e.g. acid halides by reaction with a halogenating agentsuch as a thionyl halide e.g. thionyl chloride, a phosphorous trihalidesuch as phosphorous trichloride or a phosphorous pentahalide such asphosphorous pentachloride optionally in an inert solvent such as anaromatic hydrocarbon e.g. toluene or a chlorinated hydrocarbon e.g.dichloromethane at a temperature from about 0° C. to the refluxtemperature, or may be converted into Weinreb amides of formulaArC(O)N(OMe)Me by conversion to the acid halide as just described andsubsequent reaction with an amine of formula HN(OMe)Me or a saltthereof, optionally in the presence of a base such as an organic amine,e.g. triethylamine in an inert solvent such as an aromatic hydrocarbone.g. toluene or a chlorinated hydrocarbon e.g. dichloromethane at atemperature from about 0° C. to ambient temperature.

[0238] Compounds of the invention and intermediates thereto such ascompounds of formulae (5), (6), (7), (13) and (14) may be prepared byalkylation, arylation or heteroarylation. For example, compoundscontaining a -L¹H group (where L¹ is a linker atom or group) may betreated with an alkylating agent Cy¹Z² in which Z² is a leaving atom orgroup such as a halogen atom, e.g. a fluorine, chlorine, bromine oriodine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g.trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g.p-toluenesulphonyloxy group.

[0239] The reaction may be carried out in the presence of a base such asa carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g.potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolaraprotic solvent such as an amide, e.g. a substituted amide such asdimethylformamide or an ether, e.g. a cyclic ether such astetrahydrofuran.

[0240] In another example, compounds containing a -L²H group as definedabove may be functionalised by acylation or thioacylation, for exampleby reaction with the alkylating agents just described but in which Z² isreplaced by a —C(O)Z³, C(S)Z³, —N(R²)COZ³or —N(R²)C(S)Z³ group in whichZ³ is a leaving atom or group as described for Z². The reaction may beperformed in the presence of a base, such as a hydride, e.g. sodiumhydride or an amine, e.g. triethylamine or N-methylmorpholine, in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane orcarbon tetrachloride or an amide, e.g. dimethylformamide, at for exampleambient temperature. Alternatively, the acylation may be carried outunder the same conditions with an acid (for example one of thealkylating agents described above in which Z² is replaced by a —CO₂Hgroup) in the presence of a condensing agent, for example a diimide suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide orN,N′-dicyclohexylcarbodiimide, or a benzotriazole such as[O-(7-azabenzo-triazol-1-yl)-1,1,3,3-tetramethyluronium]hexafluorophosphateadvantageously in the presence of a catalyst such as a N-hydroxycompound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole.Alternatively the acid may be reacted with a chloroformate, for exampleethylchloroformate, prior to the desired acylation reaction

[0241] In a further example compounds may be obtained by sulphonylationof a compound containing an —OH group by reaction with one of the abovealkylating agents but in which Z² is replaced by a —S(O)Hal or —SO₂Halgroup [in which Hal is a halogen atom such as chlorine atom] in thepresence of a base, for example an inorganic base such as sodium hydridein a solvent such as an amide, e.g. a substituted amide such asdimethylformamide at for example ambient temperature.

[0242] In another example, compounds containing a -L²H group as definedabove may be coupled with one of the alkylation agents just describedbut in which Z² is replaced by an —OH group in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl, diisopropyl- ordimethylazodicarboxylate.

[0243] Ester groups such as —CO₂Alk⁶ and —CO₂R⁴ in the compound offormula (1) and intermediates thereto may be converted to thecorresponding acid [—CO₂H] by acid- or base-catalysed hydrolysisdepending on the nature of the group Alk⁶ or R⁴. Acid- or base-catalysedhydrolysis may be achieved for example by treatment with an organic orinorganic acid, e.g. trifluoroacetic acid in an organic solvent e.g.dichloromethane or a mineral acid such as hydrochloric acid in a solventsuch as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide inan aqueous alcohol, e.g. aqueous methanol.

[0244] In a further example, —OR⁶ [where R⁶ represents an alkyl groupsuch as methyl group] in compounds of formula (1) and intermediatesthereto may be cleaved to the corresponding alcohol —OH by reaction withboron tribromide in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane at a low temperature, e.g. around −78° C.

[0245] Alcohol [—OH] groups may also be obtained by hydrogenation of acorresponding —OCH₂R³¹ group (where R³¹ is an aryl group) using a metalcatalyst, for example palladium on a support such as carbon in a solventsuch as ethanol in the presence of ammonium formate, cyclohexadiene orhydrogen, from around ambient to the reflux temperature. In anotherexample, —OH groups may be generated from the corresponding ester [e.g.—CO₂Alk6] or aldehyde [—CHO] by reduction, using for example a complexmetal hydride such as lithium aluminium hydride or sodium borohydride ina solvent such as methanol.

[0246] In another example, alcohol —OH groups in the compounds may beconverted to a corresponding —OR⁶ group by coupling with a reagent R⁶OHin a solvent such as tetrahydrofuran in the presence of a phosphine,e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-,or dimethylazodicarboxylate.

[0247] Aminosulphonylamino [—NHSO₂NH₂] groups in the compounds may beobtained, in another example, by reaction of a corresponding amine[—NH₂] with sulphamide in the presence of an organic base such aspyridine at an elevated temperature, e.g. the reflux temperature.

[0248] In another example compounds containing a —NHCSR⁷ or —CSNHR⁷group may be prepared by treating a corresponding compound containing a—NHCOR⁷ or —CONHR⁷ group with a thiation reagent, such as Lawesson'sReagent or P₂S₅, in an anhydrous solvent, for example a cyclic ethersuch as tetrahydrofuran, at an elevated temperature such as the refluxtemperature.

[0249] In a further example amine (—NH₂) groups may be alkylated using areductive alkylation process employing an aldehyde and a reducing agent.Suitable reducing agents include borohydrides for example sodiumtriacetoxyborohyride or sodium cyanoborohydride. The reduction may becarried out in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol,where necessary in the presence of an acid such as acetic acid at aroundambient temperature. Alternatively, the amine and aldehyde may beinitially reacted in a solvent such as an aromatic hydrocarbon e.g.toluene and then subjected to hydrogenation in the presence of a metalcatalyst, for example palladium on a support such as carbon, in asolvent such as an alcohol, e.g. ethanol.

[0250] In a further example, amine [—NH₂] groups in compounds of formula(1) and intermediates thereto may be obtained by hydrolysis from acorresponding imide by reaction with hydrazine in a solvent such as analcohol, e.g. ethanol at ambient temperature.

[0251] In another example, a nitro [—NO₂] group may be reduced to anamine [—NH₂], for example by catalytic hydrogenation using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon in a solvent such as an ether, e.g.tetrahydrofuran or an alcohol e.g. methanol, or by chemical reductionusing for example a metal, e.g. tin or iron, in the presence of an acidsuch as hydrochloric acid.

[0252] In a further example amine (—CH₂NH₂) groups in compounds offormula (1) and intermediates thereto may be obtained by reduction ofnitrites (—CN), for example by catalytic hydrogenation using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon, or Raney® nickel, in a solvent such as an ethere.g. a cyclic ether such as tetrahydrofuran or an alcohol e.g. methanolor ethanol, optionally in the presence of ammonia solution at atemperature from ambient to the reflux temperature, or by chemicalreduction using for example a metal hydride e.g. lithium aluminiumhydride, in a solvent such as an ether e.g. a cyclic ether such astetrahydrofuran, at a temperature from 0° C. to the reflux temperature.

[0253] In another example, sulphur atoms in the compounds, for examplewhen present in a group L¹ or L² may be oxidised to the correspondingsulphoxide or sulphone using an oxidising agent such as a peroxy acid,e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as ahalogenated hydrocarbon, e.g. dichloromethane, at around ambienttemperature.

[0254] In a further example N-oxides of compounds of formula (1) may ingeneral be prepared for example by oxidation of the correspondingnitrogen base using an oxidising agent such as hydrogen peroxide in thepresence of an acid such as acetic acid, at an elevated temperature, forexample around 70° C. to 80° C., or alternatively by reaction with aperacid such as peracetic acid or m-chloroperoxybenzoic acid in asolvent,such as a halogenated hydrocarbon e.g. dichloromethane or analcohol e.g. tert-butanol at a temperature from the ambient temperatureto the reflux temperature.

[0255] In another example compounds of formula (12) may be converted tofurther compounds as formula (13) in which Ar is an optionallysubstituted aromatic or heteroaromatic group for use in the synthesis offor example compounds of formula (1), using such well know and commonlyused palladium mediated reaction conditions as are to be found in thegeneral reference texts Rodd's Chemistry of Carbon Compounds, Volumes1-15 and Supplementals (Elsevier Science Publishers, 1989), Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley andSons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al,Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon), ComprehensiveOrganic Functional Group Transformations, Ed. Katritzky et al, Volumes1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed. Trost andFlemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents forOrganic Synthesis, Ed. Paquette, Volumes 1-8 (John Wiley and Sons,1995), Larock's Comprehensive Organic Transformations (VCH PublishersInc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons,5^(th) Ed., 2001).

[0256] Salts of compounds of formula (1a) or (1b) may be prepared byreaction of compounds of formula (1a) or (1b) with an appropriate basein a suitable solvent or mixture of solvents e.g. an organic solventsuch as an ether e.g. diethylether, or an alcohol, e.g. ethanol usingconventional procedures.

[0257] Where it is desired to obtain a particular enantiomer of acompound of formula (1a) or (1b) this may be produced from acorresponding mixture of enantiomers using any suitable conventionalprocedure for resolving enantiomers.

[0258] Thus for example diastereomeric derivatives, e.g. salts, may beproduced by reaction of a mixture of enantiomers of formula (1a) or (1b)e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation and the desired enantiomer recovered, e.g. bytreatment with an acid in the instance where the diastereomer is a salt.

[0259] In another resolution process a racemate of formula (1a) or (1b)may be separated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed above.

[0260] Alternatively, a particular enantiomer may be obtained byperforming an enantiomer specific enzymatic biotransformation e.g. anester hydrolysis using an esterase and then purifying only theenantiomerically pure hydrolysed acid from the unreacted ester antipode.

[0261] Chromatography, recrystallisation and other conventionalseparation procedures may also be used with intermediates or finalproducts where it is desired to obtain a particular geometric isomer ofthe invention.

[0262] The following Examples illustrate the invention. All temperaturesare in ° C.

[0263] The following abbreviations are used:

[0264] NMM—N-methylmorpholine; EtOAc—ethyl acetate;

[0265] MeOH—methanol; BOC—butoxycarbonyl;

[0266] DCM—dichloromethane; AcOH—acetic acid;

[0267] DIPEA—diisopropylethylamine; EtOH—ethanol;

[0268] Pyr—pyridine; Ar—aryl;

[0269] DMSO—dimethylsulphoxide; iPr—isopropyl;

[0270] Et₂O—diethylether; Me—methyl;

[0271] THF—tetrahydrofuran, DMF—N,N-dimethylformamide;

[0272] MCPBA—3-chloroperoxybenzoicacid NBS—N-bromosuccinimide

[0273] FMOC—9-fluorenylmethoxycarbonyl r.t.—room temperature

[0274] DBU—1,8-Diazabicyclo[5,4-0]undec-7-ene

[0275] EDC—1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

[0276] HOBT—1-hydroxybenzotriazole hydrate

[0277] All NMRs were obtained either at 300 MHz or 400 MHz.

[0278] Compounds were named with the aid of either Beilstein Autonomsupplied by MDL Information Systems GmbH, Theodor-Heuss-Allee 108,D-60486 Frankfurt, Germany or ACD Labs Name (v.5.0) supplied by AvancedChemical Development, Toronto, Canada.

[0279] LCMS retention times (RT) quoted were generated on a HewlettPackard 1100 LC/MS using the following following method: Phenomenex Luna3 μC₁₈(2) 50×4.6mm column; mobile phase A=0.1% formic acid in water; smobile phase B=0.1% formic acid in MeCN; flow rate of 0.9 mLmin⁻¹,column temperature 40° C. Gradient:- Time % B Initial  5 2.00 95 3.00 955.0  5 5.5 end

[0280] Intermediate 1

3-Benzoyl-2-fluoropyridine

[0281] To a freshly prepared solution of lithium diisopropylamide (22mmol) in dry THF (20 mL) under nitrogen and cooled to −78° was added asolution of 2-fluoropyridine (1.94 g, 20 mmol) in dry THF (10 mL). Thereaction was stirred for 2.5h at −78° before adding a solution ofN-methoxy-N-methyl benzamide (3.47 g, 21 mmol) in THF (8 mL). Thereaction mixture was allowed to warm to room temperature over 1.5 h andstir at room temperature for 1 h. The reaction was quenched with water(50 mL), extracted with EtOAc (2×50 mL), the extracts dried (MgSO₄) andconcentrated in vacuo. The crude. product was purified by chromatographyon silica (5-20% EtOAc in isohexane) to give the title compound as acolourless oil (1.05 g, 26%). δH (CDCl₃) 8.44 (1H, ddd, J 4.9, 2.0, 1.1Hz), 8.06 (1H, ddd, J 9.3, 7.4, 2.0 Hz), 7.84 (2H, dm, J 8.4 Hz), 7.66(1H, tt, J 7.4, 1.3 Hz), 7.52 (2H, tm, J 7.8 Hz), 7.38 (1H, ddd, J 6.8,4.9, 1.9 Hz). LCMS (ES⁺) RT 3.27 minutes, 202 (M+H)⁺

[0282] Intermediate 2

Ethyl 3-Phenylthieno[2,3-b]pyridine-2-carboxylate

[0283] To a solution of ethyl 2-mercaptoacetate (0.6 mL, 5.5 mmol) indry DMF (10 mL) under nitrogen and cooled with an ice bath was addedsodium hydride (220 mg of 60% dispersion in oil, 5.75 mmol). Afterhydrogen evolution had ceased the cooling bath was removed and thereaction stirred at room temperature for 30 mins. A solution ofIntermediate 1 (920 mg, 4.6 mmol) in DMF (5 mL) was added and thereaction stirred at room temperature for 3 h. The reaction was quenchedwith water (50 mL) and extracted with EtOAc (3×50 mL). The combinedEtOAc layers were washed with brine (50 mL), dried (MgSO₄) andconcentrated in vacuo to give a mixture of the title compound anduncyclised ethyl 2-(3-benzoylpyridin-2-ylsulfanyl)acetate. This crudemixture was dissolved in EtOH (10 mL) and sodium ethoxide (10 mL of 0.5Msolution in EtOH, 5.0 mmol) added. The reaction was stirred at roomtemperature for 45 mins after which time complete conversion ofuncyclised material to title compound was observed. The reaction wasdiluted with EtOAc (50 mL), washed with water (20 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by chromatographyon silica (10% EtOAc in isohexane) to give the title compound as a whitesolid (780 mg, 60%). δH (CDCl₃) 8.63 (1H, dd, J 4.5, 1.4 Hz), 7.78 (1H,dd, J 8.2, 1.5 Hz), 7.41 (3H, m), 7.33-7.32 (2H, m), 7.24 (1H, dd, J8.2, 4.6 Hz), 4.18 (2H, q, J 7.1 Hz), 1.15 (3H, t, J 7.1 Hz) LCMS (ES⁺)RT 3.90 minutes, 284 (M+H)⁺.

[0284] Intermediate 3

Ethyl 3-phenylthieno[2,3-b]pyridine-2-carboxylate N-oxide

[0285] To a solution of Intermediate 2 in DCM (10 mL) was added MCPBA(738 mg of 60% w/w, 2.57 mmol) and the reaction stirred at r.t. for 6 h.The reaction mixture was diluted with DCM (20 mL), washed with 2M NaOH(aq), dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by chromatography on silica (80% EtOAc in isohexane—EtOAc) togive the title compound as a white solid (670 mg, 90%). δH (CDCl₃) 8.36(1H, d, J 6.1 Hz), 7.55-7.49 (4H, m), 7.44-7.39 (2H, m), 7.26 (1H, dd, J8.2, 6.2 Hz), 4.20 (2H, q, J 7.1 Hz), 1.16 (3H, t, J 7.1 Hz). LCMS (ES⁺)RT3.18 minutes, 300 (M+H)⁺

[0286] Intermediate 4

Ethyl 6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0287] A mixture of Intermediate 3 (400 mg, 1.34 mmol) and aceticanhydride (20 mL) was heated to reflux for 18 h. The reaction mixturewas concentrated in vacuo and the residue co-evapourated with toluene(4×20 mL). The crude material was dissolved in THF (20 mL) and treatedwith 10% aqueous K₂CO₃ (20 mL). The reaction was stirred at roomtemperature for 18 h and then extracted with EtOAc (3×25 mL). The EtOAcextracts were dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by chromatography on silica (40-50% EtOAc in isohexane) togive the title compound as a white solid (193 mg, 48%). δH (CDCl₃) 7.48(1H, d, J 9.5 Hz), 7.43-7.36 (3H, m), 7.31-7.28 (2, m), 6.53 (1H, d, J9.5 Hz), 4.13 (2H, q, J 7.1 Hz), 1.12 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT3.25 minutes, 322 ((M+Na)⁺, 24%), 300 ((M+H)⁺, 100%).

[0288] Intermediate 5

Ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate

[0289] A mixture of 2-chloro-3-cyanopyridine (330 g), ethyl2-mercaptoacetate (361.2 g), sodium carbonate (265 g) and EtOH (1.2 L)was heated to reflux for 4.5 hours. It was then cooled to ambienttemperature, added to water (10 L) and the addition was washed in withwater (5 L). The resulting slurry was stirred for 30 minutes and then itwas filtered. The filter cake was washed with two portions of water(2×2.5 L) and dried at the pump. The solids were then dried to constantweight under vacuum at 45° to yield the title compound as a brown solid(493.1 g, 93.2%). δH (CDCl₃) 8.68 (1H, dd, J 4.7, 1.2 Hz), 7.93 (1H, dd,J 8.5, 1.2 Hz), 7.29 (1H, dd, J 8.5, 4.7 Hz), 5.90 (2H, b), 4.38 (2H, q,J 7.0 Hz), 1.40 (3H, t, J 7.0 Hz). LCMS RT 2.9 minutes, 223 (M+H)⁺

[0290] Intermediate 6

Ethyl 3-bromothieno[2,3-b]pyridine-2-carboxylate

[0291] Intermediate 5 (363.6 g) was added in portions over two hours toa mixture of copper(II) bromide (403.3 g), t-butyl nitrite (220.6 g) andacetonitrile (3.6L) stirred at a temperature of 20 to 25°. The mixturewas stirred at 20° for 2 hours before it was slowly added to 2M HCl(aq)(4.2L). The reaction mixture slurry was filtered and the solids werewashed with water (500 mL). The combined filtrate was extracted withEtOAc (8L), and the EtOAc solution was washed with 2M HCl(aq) (2.2L).The solids were dissolved in EtOAc (6L) and this solution was washedtwice with 2M HCl(aq) (4.4L and 2.2L). The two EtOAc solutions were thencombined and washed with 2M HCl(aq) (2.2L) and twice with water (2×2L).The EtOAc solution was then dried (MgSO₄), filtered and concentrated invacuo at 40 mbar and 60° to give a solid residue. This was broken up anddried to constant weight under vacuum at 45° to yield the title compoundas a brown solid (458.5 g, 97.9%). δH (DMSO-d₆) 8.89 (1H, d, J 4.7 Hz),8.47 (1H, d, J 8.6 Hz), 7.71 (1H, dd, J 8.6, 4.7 Hz), 4.46 (2H, q, J 7.2Hz), 1.40 (3H, t, J 7.2 Hz). LCMS RT 3.8 minutes, 288 (M+H)⁺

[0292] Intermediate 7

Ethyl 3-Bromothieno[2,3-b]pyridine-2-carboxylate N-oxide

[0293] To a slurry of Intermediate 6 (214 g, 0.747 Mol) in DCM (2140 mL)under nitrogen was added MCPBA (240 g @ 70%=168 g, 0.97 Mol) portionwise over 0.5 h. The reaction was then stirred at r.t. for 18 h. Thereaction mixture was quenched with water (800 mL) and pH adjusted to 8.5with 10% w/v sodium carbonate solution (1250 mL). The basic aqueouslayer was removed and the organic layer washed with water until pH 7.The organic layer was concentrated in vacuo and the crude title productwas recovered as a tan solid. The crude product was purified byslurrying in methyl tert-butyl ether (600 mL) for 1 hr at 0-5° to givethe title compound (174 g, 77%). δH (CDCl₃) 8.44 (1H, dd, J 6.2, 0.8Hz), 7.87 (1H, dd, J 8.3, 0.8 Hz), 7.48 (1H, dd, J 8.3, 6.2 Hz), 4.49(2H, q, J 7.1 Hz), 1.48 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 2.61 minutes,302(M)⁺

[0294] Intermediate 8

Ethyl 3-bromo-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0295] A mixture of Intermediate 7 (500 mg, 1.66 mmol) and DMF (10 mL)was set to stir at 0° under nitrogen. To this reaction mixture was addedtrifluoroacetic anhydride (3.49 g, 2.36 mL, 16.6 mmol) in one portionvia syringe. After stirring for 16 hours the volatiles were removed invacuo and the residue co-evaporated with toluene (2×20 mL). The crudematerial was then extracted with EtOAc (2×100 mL). The EtOAc extractswere dried (MgSO₄) and concentrated in vacuo. The crude product waspurified by a re-slurry in toluene (10 mL) to give the title compound asa beige solid (260 mg, 52%). δH (DMSO-d6) 12.20 (1H, brs), 7.75 (1H, d,J 9.0 Hz), 6.50 (1H, d, J 9.0 Hz), 4.15 (2H, q, J 7.1 Hz), 1.12 (3H, t,J 7.1 Hz). LCMS (ES⁺) RT 2.86 minutes, 302 ((M+H)⁺, 100%).MP=261.7-268.1° C.

[0296] Intermediate 9

Ethyl3-bromo-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0297] To a 2 necked round bottomed flask was added in sequenceIntermediate 8 (302 mg, 1.00 mmol), copper(II) acetate (278 mg, 1.50mmol, 150 mol %), phenylboronic acid (488 mg, 4.00 mmol), DCM (5 mL) andpyridine (158 mg, 2.00 mmol). The reaction was stirred at roomtemperature for 18 h with the exclusion of moisture. The reaction wasthen diluted with DCM (50 mL), washed with 2M HCl(aq) (50 mL), theaqueous was re-extracted with DCM (50 mL). The combined organics werethen washed with water (50 mL), dried (MgSO₄) and concentrated in vacuo.The crude product was purified by a slurry in methanol (12 mL), to givethe title compound as a beige solid (270 mg, 72%). δH (CDCl₃) 7.82 (1H,d, J 8.5 Hz), 7.70-7.62 (3H, m), 7.54-7.42 (2H, m), 6.70 (1H, d, J 8.5Hz), 4.15 (2H, q, J 7.1 Hz), 1.14 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.75minutes, 378 (M+H)⁺. MP=201.6-206.0° C.

[0298] Intermediate 10

Ethyl3-(4-fluorophenyl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0299] A mixture of Intermediate 8 (241 mg, 0.8 mmol),tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol, 10 mol %),2M K₂CO₃ (aq) (0.8 mL, 1.6 mmol) and 4-fluorophenylboronic acid inethylene glycol dimethyl ether (10 mL) was heated to reflux undernitrogen for 20 h. Solvent was removed in vacuo and the crude productpurified by chromatography on silica (10% THF in DCM) to give the titlecompound as a white solid (210 mg). LCMS (ES⁺) RT 3.24 minutes, 318(M+H)⁺.

[0300] Intermediate 11

6-Oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0301] To a solution of Intermediate 4 (5.13 g, 17 mmol) in 1:1 THFwater (200 mL) was added lithium hydroxide monohydrate (1.6 g, 37.4mmol) and the reaction stirred at r.t. overnight. The reaction wasincomplete at this time and was therefore concentrated on a rotaryevaporator by approx. half and the reaction heated at 60° for 20 h.Reaction showed complete conversion to the carboxylic acid at this time.The reaction was diluted with water (50 mL) and 2M HCl(aq) added withstirring until a precipitate had formed (pH 1-2). The solid wasfiltered, washed with several portions of water and dried in a vacuumoven to afford6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylic acid as asolid (3.0 g). LC RT 2.72 minutes. This compound was suspended inanhydrous DMF (30 mL), 1,1′-carbonyldiimidazole (2.14 g, 13.2 mmol)added and the reaction stirred for 30 mins. Ammonia (75 mL of 25%aqueous solution) was added and the reaction stirred at r.t. for 1 hbefore being concentrated in vacuo. The resultant solid was suspended in2M HCl(aq), collected by filtration and dried in a vacuum oven to givethe title compound as a white solid (2.63 g). δH (DMSO-d6) 7.63-7.49(4H, m), 7.45-7.42 (2H, m), 6.51 (1H, d, J 9.2 Hz), 6.28 (1H, bs). LCMS(ES⁺) 271 (M+H)⁺.

[0302] Intermediate 12

6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile

[0303] To a solution of Intermediate 11 (270 mg, 1.0 mmol) and pyridine(141 μL, 1.0 mmol) in dry DCM (10 mL) was added trifluoroaceticanhydride (160 μL, 2.0 mmol) and the reaction stirred at r.t. for 16 h.Solvent was removed in vacuo and the resultant solid suspended in water(30 mL) and acidified with 2M HCl(aq) (10 mL). The solid was collectedby filtration, washed with water (25 mL) and dried in vacuo to affordthe title compound as a white solid (220 mg, 87%). δH (DMSO-d6) 7.85(1H, d, J 9.1 Hz), 7.63-7.58 (5H, m), 6.69 (1H, d, J 9.1 Hz). LCMS (ES⁺)253 (M+H)⁺.

[0304] Intermediate 13

6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-sulfonyl chloride

[0305] To a solution of the compound of Example 84 (675 mg, 2.5 mmol) indry DCM (20 mL) cooled to −78° was added chlorosulfonic acid (1.72 g,14.7 mmol) over 5 mins. After 15 minutes reaction was removed from thecooling bath and stirred at r.t. for 1 h. Reaction was poured ontoice-water and extracted with DCM. The combined DCM extracts were dried(MgSO₄) and concentrated in vacuo to give the title compound as a yellowsolid (65 mg).

[0306] Intermediate 14

Ethyl3-(2,4-difluorophenyl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0307] The title compound was prepared from Intermediate 8 and2,4-difluorophenylboronic acid following the analogous proceduredescribed for Intermediate 10. This gave the title compound as a whitesolid LCMS (ES⁺) 336 (M+H)⁺.

[0308] Intermediate 15

1-Phenyl-1H-pyrrolo[3,2-b]pyridine

[0309] 1H-Pyrrolo[3,2-b]pyridine (0.5 g, 4.24 mmol), phenylboronic acid(1.03 g, 8.44 mmol), copper(II) acetate (1.54 g, 8.48 mmol), and 4Amolecular sieves (2 g), were suspended in DCM (10 mL). Triethylamine(1.19 mL, 8.5 mmol) and pyridine (0.7 mL, 8.65 mmol) were added and thereaction stirred at r.t. for three days. The reaction mixture wasdiluted with further DCM, filtered and concentrated in vacuo.Chromatography (silica, EtOAc) gave the title compound (325 mg). δH(CDCl₃) 7.80 (1H, d, J 8.2 Hz), 7.54-7.30 (7H, m), 7.15 (1H, brs), 6.88(1H, brs). LCMS (ES⁺) RT 1.20 minutes, 195 (M+H)⁺.

[0310] Intermediate 16

1-Phenyl-1H-pyrrolo[3,2-b]pyridine 4-oxide

[0311] Intermediate 15 (307 mg, 1.58 mmol) was dissolved in DCM (5 mL)and treated with MCPBA (356 mg, 2.06 mmol). After stirring for eighteenhours at r.t. the reaction was diluted with DCM, washed twice with 2Msodium hydroxide, dried (sodium sulphate) and concentrated in vacuo togive the title compound (285 mg). δH (CDCl₃) 8.15 (1H, d, J 6.2 Hz),7.55-7.47 (2H, m), 7.42-7.37 (5H, m), 7.07, (1H, dd, J 0.7, 3.5 Hz),7.01 (1H, dd, J 6.2, 8.4 Hz). LCMS (ES⁺) RT 2.527 minutes, 211 (M+H)⁺.

[0312] Intermediate 17

1-Phenyl-1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one

[0313] Intermediate 16 (273 mg, 1.3 mmol) was dissolved in DMF (3 mL)and treated at 0° with trifluoroacetic anhydride (1.8 mL, 13 mmol), wasallowed to warm to r.t. and stir for two hours. The reaction was dilutedwith toluene and concentrated in vacuo, re-dissolved in EtOH andconcentrated again to give the title compound as an olive coloured solid(420 mg). δH (CDCl₃) 8.10 (1H, d, J 9.2 Hz), 7.72-7.51 (6H, m),6.85-6.82 (2H, m). LCMS (ES⁺) RT 2.668 minutes 211 (M+H)⁺.

EXAMPLE 1 Ethyl6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0314] To an oven dried flask was added in sequence 4 Å molecular sieves(33 mg), phenylboronic acid (82 mg, 0.67 mmol), DCM (3 mL), pyridine (53mg, 0.67 mmol), Intermediate 4 (100 mg, 0.33 mmol), copper(II) acetate(6 mg, 0.033 mmol, 10 mol %) and pyridine N-oxide (34 mg, 0.36 mmol).The reaction was stirred at room temperature for 18 h with the exclusionof moisture. The reaction was then diluted with DCM (20 mL), washed with2M HCl(aq) (2×10 mL), 2M NaOH(aq) (3×10 mL), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by chromatographyon silica (DCM—1% MeOH in DCM) to give the title compound as a buffsolid (95 mg, 77%). δH (CDCl₃) 7.68-7.56 (3H, m), 7.54-7.42 (6H, m),7.40-7.38 (2H, m), 6.70 (1H, d, J 9.6 Hz), 4.15 (2H, q, J 7.1 Hz), 1.14(3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.87 minutes, 376 (M+H)⁺.

EXAMPLE 2 Ethyl7-cyclopropylmethyl-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0315] To a solution of Intermediate 4 (90 mg, 0.3 mmol) in dry DMF (3mL) was added polystyrene supported2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(PS-BEMP, 177 mg) and cyclopropylmethyl bromide (101 mg, 73 μL, 0.75mmol). The reaction was then heated to 80° under nitrogen for 18 h. Thecrude reaction mixture was filtered to remove PS-BEMP and the resinwashed with EtOAc. The filtrate was concentrated in vacuo and theresidue purified by chromatography (DCM—1% MeOH in DCM) to give thetitle compound as a brown gum (57 mg, 54%). Recrystallisation fromdiisopropyl ether gave the title compound as brown needles (30 mg). δH(CDCl₃) 7.44-7.35 (3H, m), 7.31-7.24 (4H, m), 6.45 (1H, d, J 9.5 Hz),4.14 (2H, q, J 7.1 Hz), 4.04 (2H, d, J 7.1 Hz), 1.42 (1H, m), 1.12 (3H,t, J 7.1 Hz), 0.53 (4H, m). LCMS (ES⁺) RT 4.04 minutes, 354 (M+H)⁺.

EXAMPLE 3 Ethyl7-(4-dimethylaminophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0316] To an oven dried flask was added in sequence4-dimethylaminophenylboronic acid (551 mg, 3.34 mmol), DCM (10 mL),pyridine (0.27 mL, 3.34 mmol), Intermediate 4 (500 mg, 1.67 mmol),copper(II) acetate (34 mg, 0.17 mmol, 10 mol %) and pyridine N-oxide(318 mg, 3.34 mmol). The reaction was stirred at r.t. for 24 h with theexclusion of moisture. The reaction was then diluted with DCM (20 mL),washed with saturated NH₄Cl(aq), NaHCO₃ (aq), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by chromatographyon silica (5-10% EtOAc in DCM) to give the title compound as a whitesolid (150 mg, 21%). δH (DMSO-d6) 7.51-7.49 (3H, m), 7.42-7.40 (3H, m),7.30 (2H, d, J 9.0 Hz), 6.89 (2H, d, J 9.0 Hz), 6.53 (1H, d, J 9.6 Hz),4.07 (2H, q, J 7.1 Hz), 3.31 (6H, s), 1.06 (3H, t, J 7.1 Hz). LCMS (ES⁺)RT 4.10 minutes, 419 (M+H)⁺.

General Procedure for the Preparation of Ethyl7-aryl-6-oxo-3-phenyl-6,7-tetrahydrothieno[2,3-b]pyridine-2-carboxylates

[0317] The compounds of the following Examples 4-16 were prepared byparallel synthesis using a Radleys Carousel reaction station (RadleysLtd., Saffron Walden, U.K.) following a procedure similar to thatdescribed for Example 3. Therefore to each oven dried reaction tube inthe Carousel was added a magnetic stirrer, the appropriate arylboronicacid (1.0 mmol), DCM (5 mL), pyridine (0.08 mL, 1.0 mmol), Intermediate4 (150 mg, 0.5 mmol), copper(II) acetate (10 mg, 0.05 mmol, 10 mol %)and pyridine N-oxide (95 mg, 1.0 mmol). The reactions were stirred atr.t. for 18 h with the exclusion of moisture. Each reaction was thendiluted with DCM (20 mL), washed with saturated NH₄Cl(aq), NaHCO₃(aq),dried (MgSO₄) and concentrated in vacuo. The crude products werepurified on silica eluting with 0-25% EtOAc in DCM to give the titlecompounds as solids.

EXAMPLE 4 Ethyl7-(4-methoxvphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0318] δH (DMSO-d6) 7.51-7.39 (8H, m), 7.19 (2H, d, J 9.0 Hz), 6.55 (1H,d, J 9.6 Hz), 4.08 (2H, q, J 7.1 Hz), 3.88 (3H, s), 1.05 (3H, t, J 7.1Hz). LCMS (ES⁺) RT 3.85 minutes, 406 (M+H)⁺.

EXAMPLE 5 Ethyl7-(3-methoxyphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0319] δH (DMSO-d6) 7.59 (1H, t, J 8.3 Hz), 7.51 (3H, m), 7.49 (1H, m),7.46 (2H, m), 7.18 (2H, m), 7.11 (1H, m), 6.57 (1H, d, J 9.7 Hz), 4.06(2H, q, J 7 Hz), 3.82 (3H, s), 1.07 (3H, t, J 7 Hz). LCMS (ES⁺) RT 3.87minutes, 406 (M+H)⁺.

EXAMPLE 6 Ethyl6-oxo-3-phenyl-7-(4-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0320] δH (DMSO-d6) 7.53-7.40 (10 H, m), 6.55 (1H, d, J 9.7 Hz), 4.07(2H, q, J 7.1 Hz), 2.45 (3H, s), 1.06 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT4.11 minutes, 390 (M+H)⁺.

EXAMPLE 7 Ethyl7-(5-indolyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0321] δH (DMSO-d6) 11.48 (1H, bs), 7.71 (1H, s), 7.64 (1H, d, J 8.6Hz), 7.55-7.16 (7H, m), 7.13 (1H, d, J 2.1 Hz), 6.58 (1H, m), 6.57 (1H,d, J 9.6 Hz), 4.05 (2H, q, J 7.1 Hz), 1.03 (3H, t, J 7.1 Hz). LCMS (ES⁺)RT 3.73 minutes, 415 (M+H)⁺.

EXAMPLE 8 Ethyl6-oxo-3-phenyl-7-(3-thienyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0322] δH (DMSO-d6) 8.04 (1H, dd, J 3.1, 1.4 Hz), 7.85 (1H, dd, J 5.1,3.1 Hz), 7.41 (3H, m), 7.39 (3H, m), 7.28 (1H, d, J 1.4 Hz), 6.55 (1H,d, J 9.7 Hz), 4.09 (2H, q, J 7.1 Hz), 1.06 (3H, t, J 7.1 Hz). LCMS (ES⁺)RT 3.83 minutes, 382 (M+H)⁺.

EXAMPLE 9 Ethyl6-oxo-3-phenyl-7-(4-trifluoromethoxyphenyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0323] LCMS (ES⁺) RT 4.20 minutes 460 (M+H)⁺.

EXAMPLE 10 Ethyl7-(3-fluorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0324] LCMS (ES⁺) RT 3.91 minutes 394 (M+H)⁺.

EXAMPLE 11 Ethyl7-(4-fluorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0325] LCMS (ES⁺) RT 3.88 minutes 394 (M+H)⁺.

EXAMPLE 12 Ethyl7-(4-chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0326] LCMS (ES⁺) RT 4.14 minutes 410 (M+H)⁺.

EXAMPLE 13 Ethyl7-(3-cyanophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0327] LCMS (ES⁺) RT 3.72 minutes 401 (M+H)⁺.

EXAMPLE 14 Ethyl6-oxo-3-phenyl-7-(3-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0328] LCMS (ES⁺) RT 4.09 minutes, 390 (M+H)⁺.

EXAMPLE 15 Ethyl6-oxo-3-phenyl-7-(4-trifluoromethylphenyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0329] LCMS (ES⁺) RT 4.22 minutes, 444 (M+H)⁺.

EXAMPLE 16 Ethyl7-(3-bromophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0330] LCMS (ES⁺) RT 4.24 minutes, 454 (M+H)⁺.

EXAMPLE 17 Ethyl3-(4-fluorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0331] To an oven dried flask was added in sequence phenylboronic acid(78 mg, 0.64 mmol), DCM (5 mL), pyridine (0.64 mmol), Intermediate 10(100 mg, 0.32 mmol), copper(II) acetate (0.032 mmol, 10 mol %) andpyridine N-oxide (0.35 mmol). The reaction was stirred at r.t. for 48 hwith the exclusion of moisture. The reaction was then diluted with DCM(20 mL), washed with saturated NH₄Cl(aq), dried (MgSO₄) and concentratedin vacuo. The crude product was purified by chromatography on silica(0-5% THF in DCM) to give the title compound as a white solid (75 mg).δH (CDCl₃) 7.70-7.56 (3H, m), 7.50-7.42 (3H, m), 7.40-7.32 (2H, m),7.25-7.15 (2H, m), 6.64 (1H, d, J 9.6 Hz), 4.16 (2H, q, J 7 Hz), 1.17(3H, t, J 7 Hz). LCMS (ES⁺) RT 3.77 minutes, 394 (M+H)⁺. C₂₂H₁₆NFO₃Srequires C 67.16%, H 4.10%, N 3.56%; found C 67.16%, H 4.10%, N 3.54%.

EXAMPLE 18 Ethyl7-(3-chlorophenyl)-3-(4-fluorophenyl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0332] To an oven dried flask was added in sequence3-chlorophenylboronic acid (108 mg, 0.688 mmol), dichloroethane (5 mL),pyridine (0.056 mL, 0.688 mmol), Intermediate 10 (109 mg, 0.344 mmol),copper(II) acetate (8 mg, 0.034 mmol, 10 mol %) and pyridine N-oxide (36mg, 0.38 mmol). The reaction was heated at 70° for 48 h with theexclusion of moisture. The reaction was then diluted with DCM (20 mL),washed with saturated NH₄Cl(aq), dried (MgSO₄) and concentrated invacua. The crude product was purified by chromatography on silica (0-5%THF in DCM) to give the title compound as a white solid (75 mg). LCMS(ES⁺) RT 3.93 minutes, 428 (M+H)⁺.

EXAMPLE 19 Ethyl6-oxo-7-phenyl-3-(2-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0333] 2M K₂CO₃(aq) (0.25 mL, 0.5 mmol) was added to a solution ofIntermediate 9 (100 mg, 0.266 mmol),Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.027 mmol, 10 mol %)and 2-tolylboronic acid (44 mg, 0.32 mmol) in ethylene glycol dimethylether (4 mL) and the reaction heated to reflux for 24 h under nitrogen.The mixture was diluted with water (10 mL), extracted with DCM (2×8 mL),the combined DCM extracts dried (MgSO₄) and concentrated in vacua. Thecrude product was purified by chromatography on silica (0-20% EtOAc inDCM) to give the title compound as a white solid (57 mg). δH (CDCl₃)7.60-7.48 (3H, m), 7.40 (2H, m), 7.27-7.10 (4H, m), 7.07 (1H, m), 6.51(1H, d, J 9 Hz), 4.03 (2H, q, J 7 Hz), 2.06 (3H, s), 0.99 (3H, t, J 7Hz). LCMS (ES⁺) RT 3.87 minutes, 390 (M+H)⁺. C₂₃H₁₉NO₃S requires C,70.93%; H, 4.92%; N, 3.60%; found C, 70.66%; H, 4.95%; N, 3.52%.

General Procedure for the Preparation of Ethyl3-aryl-6-oxo-7-phenyl-6,7-tetrahydrothieno[2,3-b]pyridine-2-carboxylates

[0334] The compounds of the following Examples 20-43 were prepared byparallel synthesis using a Radleys Carousel reaction station (RadleysLtd., Saffron Walden, U.K.) following a procedure similar to thatdescribed for the compound of Example 19. Each reaction tube in theCarousel was charged with the appropriate arylboronic acid (0.32 mmol,1.2 equiv.), Intermediate 9 (100 mg, 0.266 mmol),tetrakis(triphenylphosphine)palladium(0) (30 mg, 10 mol %) and amagnetic stirrer bar. Ethylene glycol dimethyl ether (4 mL) was added toeach tube followed by 2M K₂CO₃(aq) (0.25 mL, 5 mmol) and the reactionsheated to reflux under nitrogen for 24 h. Each reaction was then dilutedwith water (10 mL), extracted with DCM (2×8 mL) and the combined DCMextracts dried (MgSO₄) and concentrated in vacuo. The crude productswere purified on silica eluting with 0-25% EtOAc in DCM to give thetitle compounds as solids.

EXAMPLE 20 Ethyl6-oxo-7-phenyl-343-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0335] δH (DMSO-d6) 7.70-7.60 (3H, m), 7.56 (2H, m), 7.45 (1H, d, J 10Hz), 7.37 (1H, d, J 7 Hz), 7.36 (1H, m), 7.27 (2H, m), 6.55 (1H, d, J 10Hz), 4.03 (2H, q, J 7 Hz), 2.38 (3H, s), 1.05 (3H, t, J 7 Hz). LCMS(ES⁺) RT 3.93 minutes, 390 (M+H)⁺. C₂₃H₁₉NO₃S requires C, 70.93%; H,4.92%; N, 3.60%; found C, 70.74%; H, 4.95%; N, 3.60%.

EXAMPLE 21 Ethyl6-oxo-7-phenyl-3-(4-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0336] δH (CDCl₃) 7.70-7.50 (3H, m), 7.48-7.30 (3H, m), 7.25-7.15 (4H,m), 6.52 (1H, d, J 10 Hz), 4.07 (2H, q, J 7 Hz), 2.36 (3H, s), 1.08 (3H,t, J 7 Hz). LCMS (ES⁺) RT 3.94 minutes, 390 (M+H)⁺. C₂₃H₁₉NO₃S requiresC, 70.93%; H, 4.92%; N, 3.60%; found C, 70.42%; H, 4.92%; N, 3.58%.

EXAMPLE 22 Ethyl3-(2-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0337] δH (CDCl₃) 7.60-7.50 (3H, m), 7.48-7.30 (3H, m), 7.27 (1H, d, J10 Hz), 7.16 (1H, m), 7.01-6.94 (2H, m), 6.51 (1H, d, J 10 Hz), 4.05(2H, q, J 7 Hz), 3.71 (3H, s), 1.03 (3H, t, J 7 Hz). LCMS (ES⁺) RT 3.67minutes, 406 (M+H)⁺. C₂₃H₁₉NO₄S requires C, 68.13%; H, 4.72%; N, 3.45%;found C, 67.87%; H, 4.71%; N, 3.37%.

EXAMPLE 23 Ethyl3-(2-fluorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0338] δH (CDCl₃) 7.80-7.50 (3H, m), 7.49-7.25 (3H, m), 7.48-7.10 (4H,m), 6.55 (1H, d, J 10 Hz), 4.07 (2H, q, J 7 Hz), 1.06 (3H, t, J 7 Hz).LCMS (ES⁺) RT 3.71 minutes, 394 (M+H)⁺. C₂₂H₁₆NFO₃S requires C, 67.16%;H, 4.10%; N, 3.56%; found C, 66.99%; H, 4.05%; N, 3.49%.

EXAMPLE 24 Ethyl3-(3-chlorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0339] δH (CDCl₃) 7.68-7.58 (3H, m), 7.48-7.32 (5H, m), 7.28 (2H, m),6.66 (1H, d, J 10 Hz), 4.17 (2H, q, J 7 Hz), 1.16 (3H, t, J 7 Hz). LCMS(ES⁺) RT 3.96 minutes, 410 (M+H)⁺. C₂₂H₁₆NClO₃S requires C, 64.47%; H,3.93%; N, 3.42%; found C, 64.47%; H, 3.94%; N, 3.35%.

EXAMPLE 25 Ethyl3-(2-chlorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0340] δH (CDCl₃) 7.60-7.05 (10 H, m), 6.53 (1H, d, J 10 Hz), 4.04 (2H,q, J 7 Hz), 1.01 (3H, t, J 7 Hz). LCMS (ES⁺) RT 3.87 minutes, 410(M+H)⁺. C₂₂H₁₆NClO₃S requires C, 64.47%; H, 3.93%; N, 3.42%; found C,64.19%; H, 3.97%; N, 3.41%.

EXAMPLE 26 Ethyl3-(5-chloro-2-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0341] δH (CDCl₃) 7.60-7.45 (3H, m), 7.43-7.34 (2H, m), 7.32 (1H, dd, J9, 3 Hz), 7.26 (1H, d, J 10 Hz), 7.14 (1H, d, J 3 Hz), 6.88 (1H, d, J 8Hz), 6.53 (1H, d, J 10 Hz), 4.08 (2H, m), 3.69 (3H, s), 1.06 (3H, t J 7Hz). LCMS (ES⁺) RT 4.27 minutes, 440 (M+H)⁺.

EXAMPLE 27 Ethyl3-(4-fluoro-2-methylphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0342] δH (CDCl₃) 7.60-7.48 (3H, m), 7.45-7.37 (2H, m), 7.18 (1H, m),7.04 (1H, dd, J 8, 6 Hz), 6.98-6.89 (2H, m), 6.52 (1H, d, J 9 Hz), 4.04(2H, q, J 7 Hz), 2.06 (3H, s), 1.03 (3H, t, J 7 Hz). LCMS (ES⁺) RT 4.28minutes, 408 (M+H)⁺.

EXAMPLE 28 Ethyl3-(2,3-dichlorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0343] δH (CDCl₃) 7.60-7.53 (2H, m), 7.51-7.46 (2H, m), 7.45-7.30 (2H,m), 7.25 (1H, t, J 7.5 Hz), 7.19 (1H, d, J 10 Hz), 7.13 (1H, dd, J 7.5,1.5 Hz), 6.54 (1H, d, J 10 Hz), 4.04 (2H, m), 1.02 (3H, t, J 7 Hz). LCMS(ES⁺) RT 4.49 minutes, 444 (M+H)⁺.

EXAMPLE 29 Ethyl3-(2,4-difluorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0344] δH (CDCl₃) 7.60-7.47 (3H, m), 7.42-7.33 (2H, m), 7.31 (1H, dd, J10, 1 Hz), 7.23 (1H, q with F coupling, J 8 Hz), 6.98-6.85 (2H, m), 6.56(1H, d, J 10 Hz), 4.12 (2H, m), 1.08 (3H, t J 7 Hz). LCMS (ES⁺) RT 4.09minutes, 412 (M+H)⁺.

EXAMPLE 30 Ethyl3-(3-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0345] LCMS (ES⁺) RT 3.74 minutes, 406 (M+H)⁺.

EXAMPLE 31 Ethyl3-(4-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0346] LCMS (ES⁺) RT 3.72 minutes, 406 (M+H)⁺. C₂₃H₁₉NO₄S requires C,68.13%; H, 4.72%; N, 3.45%; found C, 67.96%; H, 4.70%; N, 3.40%.

EXAMPLE 32 Ethyl3-(3-cyanophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0347] LCMS (ES⁺) RT 3.57 minutes, 401 (M+H)⁺.

EXAMPLE 33 Ethyl3-(4-cyanophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0348] LCMS (ES⁺) RT 3.58 minutes, 401 (M+H)⁺.

EXAMPLE 34 Ethyl3-(3-fluorophenyl)-6-oxo-7-phenyl-6,7-dlihydrothieno[2,3-b]pyridine-2-carboxylate

[0349] LCMS (ES⁺) RT 3.78 minutes, 394 (M+H)⁺. C₂₂H₁₆NFO₃S requires C,67.16%; H, 4.10%; N, 3.56%; found C, 67.06%; H, 4.10%; N, 3.54%.

EXAMPLE 35 Ethyl3-(4-chlorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0350] LCMS (ES⁺) RT 4.05 minutes, 410 (M+H)⁺. C₂₂H₁₆NClO₃S requires C,64.47%; H, 3.93%; N, 3.42%; found C, 64.31%; H, 3.93%; N, 3.45%.

EXAMPLE 36 Ethyl3-(2,4-dichlorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0351] LCMS (ES⁺) RT 4.70 minutes, 445 (M+H)⁺.

EXAMPLE 37 Ethyl3-(2,5-dichlorophenyl-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0352] LCMS (ES⁺) RT 4.57 minutes, 445 (M+H)⁺.

EXAMPLE 38 Ethyl3-(5-fluoro-2-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0353] LCMS (ES⁺) RT 3.98 minutes, 424 (M+H)⁺.

EXAMPLE 39 Ethyl3-(2,6-dimethylphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0354] LCMS (ES⁺) RT 4.04 minutes, 404 (M+H)⁺.

EXAMPLE 40 Ethyl6-oxo-7-phenyl-3-(3-pyridyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0355] LCMS (ES⁺) RT 3.00 minutes, 377 (M+H)⁺.

EXAMPLE 41 Ethyl6-oxo-7-phenyl-3-(2-trifluoromethylphenyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0356] LCMS (ES⁺) RT 3.80 minutes, 444 (M+H)⁺.

EXAMPLE 42 Ethyl6-oxo-7-phenyl-3-(3-trifluoromethylphenyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0357] LCMS (ES⁺) RT 3.97 minutes, 444 (M+H)⁺.

EXAMPLE 43 Ethyl6-oxo-7-phenyl-3-(4-trifluoromethylphenyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylateLCMS (ES⁺) RT 3.99 minutes, 444 (M+H)⁺. EXAMPLE 44 Ethyl6-oxo-3-phenyl-7-(3-pyridinyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0358] A mixture of Intermediate 4 (299 mg, 1.0 mmol),pyridine-3-boronic acid (246 mg, 2.0 mmol), pyridine-N-oxide (115 mg,1.2 mmol), copper(II) acetate (182 mg, 1.0 mmol) and pyridine (0.160 mL,2.0 mmol) in DCM (20 mL) was stirred at r.t. for 3 days. The mixture wasdiluted with DCM (30 mL) and washed with saturated NH₄Cl(aq) plusammonia (pH 10, 2×100 mL), dried (Na₂SO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography on silica (3% MeOHin DCM) to give the title compound as a white solid (35 mg, 9%). δH(CDCl₃) 9.00 (1H, d, J 4.5 Hz), 8.95 (1H, s), 8.01 (1H, ddd, J 1.5, 2.4,8.1 Hz), 7.76 (1H, dd, J 4.7, 8.1 Hz), 7.68-7.52 (4H, m), 7.55-7.52 (2H,m), 6.77 (1H, d, J 9.7 Hz), 4.31 (2H, q, J 7.1 Hz), 1.30 (3H, t, J 7.1Hz). m/z (ES⁺) 377.0 (M+H)⁺.

EXAMPLE 45 Ethyl7-benzyl-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0359] Sodium hydride (32 mg of 60% w/w suspension in oil, 0.8 mmol, 1.2equiv.) was added to a solution of Intermediate 4 (200 mg, 0.67 mmol) inanhydrous DMF (5 mL) under nitrogen and cooled with an ice bath. Thereaction was stirred for 5 minutes before adding benzyl bromide (0.12mL, 1.0 mmol, 1.5 equiv.). The reaction was heated at 60° for 18 h. Thereaction was partitioned between water and EtOAc, the EtOAc extractswere dried (MgSO₄) and then concentrated in vacuo. The crude residue waspurified by chromatography on silica (0-20% EtOAc in DCM) to give thetitle compound as an off-white solid (80 mg). δH (CDCl₃) 7.60-7.20 (11H,m), 6.51 (1H, d, J 10 Hz), 5.33 (2H, s), 4.08 (2H, q, J 7 Hz), 1.07 (3H,t, J 7 Hz). LCMS (ES⁺) RT 4.05 minutes, 390 (M+H)⁺.

General Procedure for the Preparation of Ethyl7-alkyl-6-oxo-3-phenyl-6,7-tetrahydrothieno[2,3-b]pyridine-2-carboxylates

[0360] The compounds of the following Examples 46-56 were prepared byparallel synthesis using a Radleys Carousel reaction station (RadleysLtd., Saffron Walden, U.K.) following a procedure similar to thatdescribed for Example 2. Each reaction tube in the Carousel was chargedwith the appropriate alkyl or arylalkyl halide (1.5 mmol, 1.5 equiv.),Intermediate 4 (200 mg, 0.67 mmol), polystyrene supported2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(PS-BEMP, 364 mg, 0.8 mmol, 1.2equiv.) and a magnetic stirrer bar.Anhydrous DMF (4 mL) was added to each tube and the reactions stirred at65° under nitrogen for 48 h. Each reaction was partitioned between waterand DCM and the combined DCM extracts dried (MgSO₄) and concentrated invacuo. The crude products were purified on silica eluting with 0-20%EtOAc in DCM to give the title compounds as solids.

EXAMPLE 46 Ethyl7-(cyclohexylmethyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0361] δH (CDCl₃) 7.40-7.35 (3H, m), 7.27-7.24 (3H, m), 6.42 (1H, d, J10 Hz), 4.12 (2H, q, J 7 Hz), 3.95 (2H, d, J 7.5 Hz), 2.08-2.05 (1H, m),1.67-1.53 (5H, m), 1.16-1.09 (5H, m), 1.11 (3H, t, J 7 Hz). LCMS (ES⁺)RT 5.17 minutes, 396 (M+H)⁺.

EXAMPLE 47 Ethyl6-oxo-7-(1-phenylethyl)-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0362] δH (CDCl₃) 7.30-7.18 (11H, m), 6.72 (1H, m), 6.49 (1H, d, J 10Hz), 4.05-3.99 (2H, m), 1.91 (3H, d, J 7 Hz), 1.01 (3H, t, J 7 Hz). LCMS(ES⁺) RT 4.29 minutes, 404 (M+H)⁺.

EXAMPLE 48 Ethyl7-(3-methoxybenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0363] δH (CDCl₃) 7.40-7.35 (3H, m), 7.29 (1H, d, J 10 Hz), 7.25-7.17(3H, m), 6.93 (1H, m), 6.90 (1H, bs), 6.77 (1H, m), 6.50 (1H, d, J 10Hz), 5.30 (2H, s), 4.08 (2H, q, J 7 Hz), 3.72 (3H, s), 1.07 (3H, t, J 7Hz). LCMS (ES⁺) RT 4.09 minutes, 420 (M+H)⁺.

EXAMPLE 49 Ethyl7-(2,6-difluorobenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0364] δH (CDCl₃) 7.41-7.35 (3H, m), 7.29-7.15 (4H, m), 6.85 (2H, t, J 8Hz), 6.45 (1H, d, J 10 Hz), 5.45 (2H, s), 4.08 (2H, q, J 7 Hz), 1.06(3H, t, J 7 Hz). LCMS (ES⁺) RT 4.06 minutes, 426 (M+H)⁺.

EXAMPLE 50 Ethyl7-(3-methylbutyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0365] LCMS (ES⁺) RT 4.64 minutes, 370 (M+H)⁺.

EXAMPLE 51 Ethyl7-allyl-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0366] LCMS (ES⁺) RT 3.84 minutes, 340 (M+H)⁺.

EXAMPLE 52 Ethyl6-oxo-7-(2-phenylethyl)-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0367] LCMS (ES⁺) RT 3.45 minutes, 404 (M+H)⁺.

EXAMPLE 53 Ethyl7-(2-chlorobenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0368] LCMS (ES⁺) RT 4.40 minutes, 424 (M+H)⁺.

EXAMPLE 54 Ethyl7-(3-chlorobenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0369] LCMS (ES⁺) RT 4.45minutes, 424 (M+H)⁺.

EXAMPLE 55 Ethyl7-(4-chlorobenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridlne-2-carboxylate

[0370] LCMS (ES⁺) RT 4.49 minutes, 424 (M+H)⁺.

EXAMPLE 56 Ethyl7-(2-morpholinoethyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0371] This compound was purified by chromatography on silica elutingwith 0-20% THF in DCM. LCMS (ES⁺) RT 2.52 minutes, 413 (M+H)⁺.

EXAMPLE 57 Ethyl7-(4-bromophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0372] To an oven dried flask was added in sequence 4-bromophenylboronicacid (5.0 g, 25 mmol), DCM (100 mL), pyridine (2.7 mL), Intermediate 4(3.74 g, 12.5 mmol), copper(II) acetate (2.26 g, 12.5 mmol) and pyridineN-oxide (1.46 g). The reaction was stirred at room temperature for 72 hwith the exclusion of moisture. The reaction was then diluted with DCM(100 mL), washed with 2M HCl(aq), NaHCO₃ (aq), dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by chromatographyon silica (0-20% EtOAc in DCM) to give the title compound as a whitesolid (2.03 g). δH (DMSO-d6) 7.89 (2H, J 8.7 Hz), 7.58 (2H, J 8.7 Hz),7.53-7.49 (3H, m), 7.46 (1H, d, J 9.7 Hz), 7.42-7.40 (2H, m), 6.57 (1H,d, J 9.7 Hz), 4.07 (2H, q, J 7.1 Hz), 1.06 (3H, t, J 7.1 Hz). LCMS (ES⁺)RT 4.25 minutes, 456 (M+H)⁺.

EXAMPLE 58 Ethyl7-(4-morpholinophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0373] To a mixture of the compound of Example 57 (100 mg, 0.22 mmol),caesium carbonate (101 mg, 0.31 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol, 10mol %) and 2,2′-bis(diphenylphosphino)-1-1′-binaphthyl (BINAP) (21 mg,0.033 mmol, 15 mol %) in toluene (2 mL) and under nitrogen was addedmorpholine (0.024 mL, 0.27 mmol). The reaction mixture was heated to100° for 18 h. Solvent was removed in vacuo and the crude productpurified by chromatography on silica (0-20% THF in DCM) to give thetitle compound as a white solid (40 mg).

[0374] δH (CDCl₃) 7.50-7.18 (8H, m), 7.01 (2H, d, J 9 Hz), 6.52 (1H, d,J 10 Hz), 4.06 (2H, q, J 7 Hz), 3.82 (4H, m), 3.22 (4H, m), 1.06 (3H, t,J 7 Hz). LCMS (ES⁺) RT 3.82 minutes, 461 (M+H)⁺.

EXAMPLE 596-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylic acid

[0375] To a solution of the compound of Example 1 (4.53 g, 12.1 mmol) in2:1 THF-water (150 mL) was added LiOH.H₂O (1.50 g, 36.2 mmol) and thereaction stirred for 36 h at r.t. The reaction was diluted with water 50mL and 2M HCl(aq) added with stirring until a precipitate had formed (pH1-2). The solid was filtered, washed with several portions of water anddried in a vacuum oven (50° C.) to afford the title compound as a whitesolid (4.2 g). δH (DMSO-d6) 13.00 (1H, bs), 7.70-7.40 (11H, m), 6.55(1H, d, J 10 Hz). LCMS (ES⁺) RT 3.10 minutes, 348 (M+H)⁺.

EXAMPLE 602-[(4-Methylpiperazino)carbonyl]-3,7-diphenylthieno[2,3-b]pyridin-6(7H)-one

[0376] To a suspension of the compound of Example 59 (100 mg, 0.29 mmol)in DCM (2 mL) was added EDC (67 mg, 0.348 mmol) and HOBT (43 mg, 0.32mmol) and the mixture stirred at r.t. for 15 minutes. A solutionN-methyl piperazine (28 mg, 0.32 mmol) in DCM (0.5 mL) was added and thereaction stirred at r.t. for 18 h. The reaction mixture was diluted withDCM (10 mL), washed with water (2×5 mL), dried (MgSO₄) and concentratedin vacuo. The crude product was purified by chromatography on silica(0-20% THF in DCM) to give the title compound as an off-white solid (82mg). δH (DMSO-d6) 7.67 (1H, dd, J 10, 1 Hz), 7.62-7.52 (3H, m),7.51-7.40 (5H, m), 7.35-7.31 (2H, m), 6.51 (1H, dd, J 10, 1 Hz), 2.44(8H, m), 1.88 (3H, s). LCMS (ES⁺) RT 2.18 minutes, 430 (M+H)⁺.

EXAMPLE 61N-Ethyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0377] EDC (66 mg, 0.35 mmol) and HOBT (43 mg, 0.32 mmol) were added tothe compound of Example 59 (100 mg, 0.29 mmol) in DCM (2 mL). After 15min ethylamine hydrochloride (26 mg, 0.32 mmol) and NMM (0.070 mL, 0.63mmol) were added and the reaction mixture was stirred at r.t. overnight.Water (2 mL) and DCM (2 mL) were added, the suspension filtered througha hydrophobic frit and the organic phase concentrated in vacuo. Thecrude product was purified by column chromatography on silica (1% MeOHin DCM) to give the title compound as a white solid (95 mg, 88%). δH(DMSO-d6) 7.69-7.61 (3H, m), 7.59-7.49 (3H, m), 7.45 (1H, d, J 9.6 Hz),7.44-7.42 (4H, m), 7.05 (1H, t, J 5.4 Hz), 6.54 (1H, d, J 9.6 Hz), 3.03(2H, q, J 7.1 Hz), 0.84 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.33 minutes,375.0 (M+H)⁺.

[0378] The following compounds of Examples 62-74 were prepared from thecompound of Example 59 and the appropriate amine or amine hydrochlorideby the method of Example 61.

EXAMPLE 62N-(3-Hydroxypropyl)-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0379] LCMS (ES⁺) RT 2.99 minutes, 405.0 (M+H)⁺

EXAMPLE 636-Oxo-3,7-diphenyl-N-[2-(1-pyrrolidinyl)ethyl]-6,7-dihydrothieno[2,3-b]pyrldine-2-carboxamide

[0380] LCMS (ES⁺) RT 2.29 minutes, 444.1 (M+H)⁺

EXAMPLE 646-Oxo-3,7-diphenyl-N-(2-piperidinoethyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0381] LCMS (ES⁺) RT 2.33 minutes, 458.1 (M+H)⁺

EXAMPLE 65N-(3-Methoxypropyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0382] LCMS (ES⁺) RT 3.28 minutes, 419.0 (M+H)⁺

EXAMPLE 66N-(2-Methoxyethyl)-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0383] LCMS (ES⁺) RT 3.24 minutes, 405.0 (M+H)⁺

EXAMPLE 673,7-Diphenyl-2-(1-pyrrolidinylcarbonyl)thieno[2,3-b]pyridin-6(7H)-one

[0384] LCMS (ES⁺) RT 3.43 minutes, 401.0 (M+H)⁺

EXAMPLE 68N-[3-(1H-Imidazol-1-yl)propyl]-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0385] LCMS (ES⁺) RT 2.28 minutes, 455.1 (M+H)⁺

EXAMPLE 69N-(2-Morpholinoethyl)-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0386] LCMS (ES⁺) RT 2.28 minutes, 460.1 (M+H)⁺

EXAMPLE 70N-[3-(4-Methylpiperazino)propyl]-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0387] LCMS (ES⁺) RT 2.16 minutes, 487.1 (M+H)⁺

EXAMPLE 71N-(3-Morpholinopropyl)-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0388] LCMS (ES⁺) RT 2.26 minutes, 474.1 (M+H)⁺

EXAMPLE 72N,N-Diethyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0389] LCMS (ES⁺) RT 3.62 minutes, 403.0 (M+H)⁺

EXAMPLE 73N,N-Dimethyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0390] LCMS (ES⁺) RT 3.17 minutes, 375.0 (M+H)⁺

EXAMPLE 74N-Methyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0391] LCMS (ES⁺) RT 3.15 minutes, 361.0 (M+H)⁺

EXAMPLE 756-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0392] 1,1′-Carbonyidiimidazole (51 mg, 0.32 mmol) was added to thecompound of Example 59 (100 mg, 0.29 mmol) in DMF (2 mL). After 15 minaq. ammonia (0.190 mL, 25% solution, 3.0 mmol) was added and thesolution stirred at r.t. overnight. The mixture was concentrated invacuo and azeotroped twice with heptane. The crude product was purifiedby column chromatography on silica (3% MeOH in DCM) to give the titlecompound as a white solid (74 mg, 74%). δH (DMSO-d6) 7.87-7.76 (3H, m),7.75-7.68 (5H, m), 7.64-7.61 (2H, m), 7.54 (1H, d, J 9.6 Hz), 6.69 (1H,d, J 9.6 Hz), 6.25 (2H, br s). LCMS (ES⁺) RT 2.95 minutes, 347.0 (M+H)⁺.

EXAMPLE 76N-Methoxy-N-methyl-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0393] N,O-Dimethylhydroxylamine hydrochloride (31 mg, 0.32 mmol) wasadded to a mixture of the compound of Example 59 (101 mg, 0.29 mmol),HOBT (55 mg, 0.41 mmol), EDC (78 mg, 0.41 mmol) and NMM (0.090 mL, 0.81mmol) in DCM (3 mL). The mixture was stirred for 6 h at roomtemperature. DCM was added and the mixture washed with 2M HCl(aq). Theorganic phase was re-extracted with DCM. The combined organics weredried (Na₂SO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography on silica (3.5% MeOH in DCM) to give the titlecompound as a white solid (95 mg, 84%). δH (DMSO-d6) 7.48-7.35 (3H, m),7.34-7.30 (3H, m), 7.29-7.23 (3H, m), 7.16-7.13 (2H, m), 6.33 (1H, d, J9.6 Hz), 3.26 (3H, s), 2.79 (3H, s). LCMS (ES⁺) RT 3.27 minutes, 391.0(M+H)⁺.

EXAMPLE 776-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile

[0394] A mixture of cyanuric chloride (28 mg, 0.15 mmol) and thecompound of Example 75 (52 mg, 0.15 mmol) in DMF (1.5 mL) was heated at110° for 18 h. Two further portions of cyanuric chloride (14 mg, 0.075mmol) were added and heating continued for a further 26 h. Water wasadded and the precipitate filtered off, washed with water and dried. Thecrude product was purified by column chromatography on silica (1% THF inDCM) to give the title compound as a white solid (35 mg, 71%). δH(DMSO-d6) 7.78 (1H, d, J 9.6 Hz), 7.71-7.67 (1H, m), 7.66-7.64 (1H, m),7.64-7.59 (7H, m), 7.59-7.58 (1H, m), 6.67 (1H, d, J 9.6 Hz). LCMS (ES⁺)RT 3.65 minutes, 329 (M+H)⁺.

EXAMPLE 782-(1-Hydroxy-1-methylethyl)-3,7-diphenylthieno[2,3-b]pyridin-6(7H)-one

[0395] A solution of methyl magnesium iodide (0.084 mL of a 3M solutionin ether, 0.25 mmol) was added drop-wise to a solution of the compoundof Example 1 (47 mg, 0.13 mmol) in DCM (2 mL) at 0°. The mixture wasallowed to warm to r.t. and stirred for 18 h. More methyl magnesiumiodide (0.084 mL of a 3M solution in ether, 0.25 mmol) was added at 0°and the mixture stirred at r.t. for 1 h. DCM and NH₄Cl(aq) were added,the aqueous phase re-extracted with DCM and the combined organicextracts dried (Na₂SO₄) and concentrated in vacuo. The crude product waspurified by column chromatography on silica (1% MeOH in DCM) to give thetitle compound as a yellow solid (36 mg, 80%). δH (DMSO-d6) 7.74-7.64(3H, m), 7.60-7.52 (5H, m), 7.39 (2H, dd, J 7.8, 1.6 Hz), 7.10 (1H, d, J9.5 Hz), 6.45 (1H, d, J 9.5 Hz), 2.58 (6H, s). LCMS (ES⁺) RT 3.46minutes, 362 (M+H)⁺.

EXAMPLE 79 2-(Hydroxymethyl)-3,7-diphenylthieno[2,3-b]pyridin-6(7H)-one

[0396] Lithium borohydride (0.100 mL, 2M in THF, 0.2 mmol) was added toa solution of the compound of Example 1 (75 mg, 0.198 mmol) in THF (2mL) and the reaction mixture was stirred at r.t. overnight. Two furtherportions of lithium borohydride (0.100 mL, 2M in THF, 0.198 mmol) wereadded and the mixture stirred for a further 6 h. The reaction wasquenched by the addition of 2M HCl(aq) and the mixture neutralised bythe addition of Na₂CO₃ The resulting precipitate was filtered off,washed with water and dried to give the title compound as a white solid(55 mg, 97%). δH (DMSO-d6) 7.68-7.41 (11H, m), 6.49 (1H, d, J 9.5 Hz),5.57 (1H, br s), 4.50 (2H, br s). LCMS (ES⁺) RT 3.10 minutes, 334.0(M+H)⁺.

EXAMPLE 80 tert-ButylN-(6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)carbamate

[0397] Triethylamine (0.076 mL, 0.55 mmol) and diphenylphosphoryl azide(0.1 19 mL, 0.55 mmol) were added to a solution of the compound ofExample 59 (174 mg, 0.5 mmol) in dry tert-butanol (5 mL) and the mixtureheated under reflux under nitrogen for 6 h. The cooled mixture waspoured into saturated NaHCO₃(aq) (20 mL) and extracted with DCM (2×20mL). The combined organic fractions were dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica (EtOAc) to give the title compound (1 96 mg,94%). δH (CDCl₃) 7.5-7.25 (11H, m), 6.70 (1H, br s), 6.46 (1H, d, J 9Hz), 1.29 (9H, s). m/z (ES⁺) 419 (M+H)⁺.

EXAMPLE 81 2-Amino-3,7-diphenylthieno[2,3-b]pyridin-6(7H)-one

[0398] Trifluoroacetic acid (2 mL) was added to a solution of thecompound of Example 80 (170 mg, 0.406 mmol) in DCM (2 mL) and thereaction mixture stirred for 2 h at r.t. The mixture was added tosaturated NaHCO₃(aq) (20 mL) and the product extracted with DCM (2×20mL). The combined organic fractions were dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by flash columnchromatography on silica (EtOAc), followed by radial chromatography (20%EtOH in DCM) to give the title compound as a buff solid (30 mg, 23%). δH(CDCl₃) 7.8-7.3 (13H, m), 6.58 (1H, d, J 9 Hz). m/z (ES⁺) 319 (M+H)⁺.

EXAMPLE 82 tert-ButylN-methylsulfonyl-N-(6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)carbamate

[0399] Sodium bis(trimethylsilyl) amide (0.25 mL of a 1M solution inTHF, 0.25 mmol) was added to a solution of the compound of Example 80(105 mg, 0.25 mmol) in dry THF (5 mL) under a nitrogen atmosphere at 0°.After 30 min methane sulfonyl chloride (28.6 mg, 0.25 mmol) was added.The reaction mixture was allowed to warm to r.t. over 1 h then pouredinto saturated NaHCO₃(aq) (20 mL) and the product extracted with DCM(2×20 mL). The combined organic fractions were dried (MgSO₄), filteredand concentrated in vacuo. The crude product was purified by radialchromatography on silica (EtOAc) to give the title compound (115 mg,92%). δH (CDCl₃) 7.6-7.28 (11H, m), 6.55 (1H, d, J 9 Hz), 2.68 (3H, s),1.32 (9H, s). m/z (ES⁺) 497 (M+H)⁺.

EXAMPLE 83N-(6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)methanesulfonamide

[0400] Trifluoroacetic acid (2.5 mL) was added to a solution of thecompound of Example 82 (105 mg, 0.212 mmol) in DCM (2.5 mL) and thereaction mixture stirred for 2 h at r.t. The mixture was added tosaturated NaHCO₃ solution (20 mL) and the product extracted with DCM(2×20 mL). The combined organic fractions were dried (MgSO₄), filteredand concentrated in vacuo. The crude product was purified by radialchromatography on silica (EtOAc) to give the title compound (62 mg,74%). δH (CDCl₃) 7.6-7.25 (11H, m), 6.58 (1H, d, J 9 Hz), 6.31 (1H, brs), 2.53 (3H, s). m/z (ES⁺) 397 (M+H)⁺.

EXAMPLE 84 3,7-Diphenylthieno[2,3-b]pyrldin-6(7H)-one

[0401] 2M HCl(aq) (10 mL) was added to a solution of the compound ofExample 59 (300 mg, 0.864 mmol) in dioxane (30 mL) and the mixtureheated at reflux for 16 h. The cooled reaction mixture was poured into10% NaOH(aq) (50 mL) and extracted with DCM (2×50 mL) The combinedorganic fractions were dried (Na₂SO₄), filtered and concentrated invacuo to give the title compound as a white solid in quantitative yield.δH (CDCl₃) 7.83 (1H, d, J 9 Hz), 7.7-7.35 (10 H, m), 6.80 (1H, s), 6.67(1H, d, J 9 Hz). m/z (ES⁺) 304 (M+H)⁺.

EXAMPLE 85N-(6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)acetamide

[0402] Acetyl chloride (0.10 mL) was added to a solution of the compoundof Example 81 (116 mg, 0.38 mmol) and pyridine (0.10 mL) in DCM (5 mL)and the mixture stirred at r.t. overnight. The reaction was quenchedwith MeOH and partitioned between DCM and water. The organic phase wasdried (MgSO₄) and concentrated in vacuo. The crude product was purifiedby column chromatography on silica (0-5% MeOH in EtOAc) to give thetitle compound (39 mg, 21 %). δH(CDCl₃) 7.65 (1H, br s), 7.63-7.39 (11H,m), 6.63 (1H, d, J 9.5 Hz), 1.99 (3H, s). LCMS (ES⁺) RT 2.621 minutes,361 (M+H)⁺.

EXAMPLE 861-Methyl-N-(6-oxo-3.7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-vI)-1H-imidazole-4-sulfonamide

[0403] 1-Methyl-1H-imidazole-4-sulfonyl chloride (96 mg, 0.53 mmol) wasadded to a solution of the compound of Example 81 (136 mg, 0.44 mmol)and pyridine (52 mg, 0.66 mmol) in DCM (10 mL) and the reaction mixturestirred at r.t. overnight. The mixture was partitioned between DCM andNaHCO₃(aq). The organic phase was dried (MgSO₄) and concentrated invacuo. The crude product was purified by column chromatography on silica(10% MeOH in DCM) to give the title compound (75 mg, 37%). δH (MeOH-d4)7.60-7.48 (5H, m), 7.38-7.25 (6H, m), 7.23 (1H, m), 7.13 (2H, m), 6.48(1H, d, J 9.5 Hz), 3.55 (3H, s). LCMS (ES⁺) RT 2.90 minutes, 463 (M+H)⁺.

EXAMPLE 87 Ethyl7-[4-(benzyloxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0404] A mixture of Intermediate 4 (2.50 g, 8.36 mmol),4-(benzyloxy)phenylboronic acid (2.86 g, 12.5 mmol), copper(II) acetate(3.04 g, 16.7 mmol) and pyridine (2.7 mL, 33.4 mmol) in DCM (200 mL) wasstirred at r.t. for 5 days. The mixture was diluted with DCM (100 mL)and filtered through celite. The filtrate was washed with 2M HCl(aq)(2×200 mL), dried (Na₂SO₄) and concentrated in vacuo. The crude productwas purified by column chromatography on silica (3% MeOH in DCM) to givethe title compound as a white solid (1.35 g, 34%). δH (CDCl₃) 7.52-7.35(13H, m), 7.21-7.16 (2H, m), 6.60 (1H, d, J 9.6 Hz), 5.15 (2H, s), 4.14(2H, q, J 7.1 Hz), 1.13 (3H, t, J 7.1 Hz). m/z (ES⁺) 482.1 (M+H)⁺.

EXAMPLE 88 Ethyl7-[4-(hydroxvmethyl)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0405] A mixture of Intermediate 4 (300 mg, 1.0 mmol),4-(hydroxymethyl)phenyl boronic acid (304 mg, 12.5 mmol), copper(II)acetate (913 mg, 5.0 mmol) and pyridine (0.404 mL, 5.0 mmol) in DCM (7mL) was stirred at r.t. for 3 days. The mixture was diluted with DCM,washed with HCl (2M), dried (MgSO₄) and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica (50-100% EtOAcin isohexane) to give the title compound as a white solid (255 mg, 63%).δH (CDCl₃) 7.54 (2H, d, J 8.9 Hz), 7.44-7.28 (8H, m), 6.53 (1H, d, J10.6 Hz), 4.72 (2H, s), 4.06 (2H, q, J 7.1 Hz), 1.05 (3H, t, J 7.1 Hz).LCMS (ES⁺) RT 3.45 minutes, 406 (M+H)⁺.

EXAMPLE 89 Ethyl7-(4-hydroxyphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0406] A mixture of Intermediate 4 (554 mg, 1.86 mmol), 4-hydroxyphenylboronic acid (511 mg, 3.71 mmol), copper(II) acetate (37 mg, 0.187mmol), pyridine-N-oxide (350 mg, 3.71 mmol) and pyridine (0.370 mL, 3.71mmol) in DCM (20 mL) was stirred at r.t. overnight. The reaction mixturewas diluted with DCM, washed with NH₄Cl(aq) and water, dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography on silica (5% MeOH in DCM) to give the title compound asa cream solid (484 mg, 73%). δH (DMSO-d6) 10.06 (1H, s), 7.54-7.50 (3H,m), 7.47-7.45 (3H, m), 7.37 (2H, d, J 9 Hz), 7.02 (2H, d, J 9 Hz), 6.58(1H, d, J 10 Hz), 4.11 (2H, q, J 7 Hz), 1.09 (3H, t, J 7 Hz). LCMS (ES⁺)392.1 (M+H)⁺.

EXAMPLE 90 Ethyl7-[4-(2-hydroxyethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0407] 2-Bromoethanol (0.148 mL, 2.08 mmol) was added to the compound ofExample 89 (370 mg, 0.95 mmol) and Cs₂CO₃ (342 mg, 1.04 mmol) in DMF (5mL) and the mixture heated at 80° for 2 days. The solvent was removed invacuo and the residue partitioned between EtOAc and HCl (10%). Theaqueous phase was extracted with EtOAc (2×20 mL). The combined organicswere washed with brine, dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by column chromatography on silica (2% to 10%MeOH in DCM) to give the title compound (73 mg, 18%). δH (CDCl₃)7.44-7.28 (8H, m), 7.07 (2H, d, J 8 Hz), 6.52 (1H, d, J 9.6 Hz),4.12-3.93 (6H, m), 1.06 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.42 minutes,436 (M+H)⁺.

EXAMPLE 91 Ethyl7-{4-[2-(2-methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0408] Pyridine (0.136 mL, 1.68 mmol) was added to a mixture of thecompound of Example 90 (73 mg, 0.168 mmol) and tosylchloride (40 mg,0.21 mmol) in DCM (2 mL) at 0°. The reaction mixture was stirred at 0°for 5 h then allowed to warm to r.t. The mixture was diluted with DCM(20 mL), washed with 2M HCl(aq), 10% NaOH(aq) and brine, dried (MgSO₄)and concentrated in vacuo. The crude product was purified by columnchromatography on silica (50 to 80% EtOAc in isohexane) to give theintermediate tosylate, ethyl7-[4-(2-[(4-methylphenyl)sulfonyl]oxyethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydro-1-benzothiophene-2-carboxylate,as a solid (73 mg, 12%). δH(CDCl₃) 7.78 (2H, d, J 8.6 Hz), 7.43-7.27(10H, m), 6.93 (2H, d, J 8.6 Hz), 6.52 (1H, d, J 9.6 Hz), 4.38-4.35 (2H,m), 4.18-4.15 (2H, m), 4.07 (2H, q, J 7.1 Hz), 2.40 (3H, s), 1.06 (3H,t, J 7.1 Hz). LCMS (ES⁺) RT 4.15 minutes, 590 (M+H)⁺.

[0409] A mixture of this tosylate (70 mg, 0.12 mmol), 2-methylimidazole(11 mg, 0.13 mmol) and Cs₂CO₃ (43 mg, 0.13 mmol) in DMF (1 mL) washeated at 80° for 6 h. The solvent was removed in vacuo and the residuepartitioned between DCM (15 mL) and NaHCO₃(aq) (15 mL). The organicphase was extracted with DCM (2×10 mL). The combined organics were dried(MgSO₄) and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica (10% MeOH in DCM) to give the titlecompound (20 mg, 34%). δH(CDCl₃) 7.43-7.28 (8H, m), 7.19-7.15 (2H, m),7.01-6.90 (2H, m), 6.51 (1H, d, J 9.6 Hz), 4.25-4.20 (4H, br m), 4.06(2H, q, J 7.1 Hz), 2.43 (3H, s), 1.05 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT2.62 minutes, 500 (M+H)⁺.

EXAMPLE 92 Ethyl7-[4-(2-morpholinoethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0410] To a mixture of the compound of Example 89 (100 mg, 0.256 mmol)and caesium carbonate (202 mg, 0.62 mmol) in dry DMF (5 mL) was added2-(chloroethyl)morpholine hydrochloride (58 mg, 0.31 mmol) and thereaction heated at 60° under nitrogen for 48 h. The reaction waspartitioned between water and EtOAc, the EtOAc extracts dried (MgSO₄)and concentrated in vacuo. The crude product was then purified by columnchromatography on silica eluting with 0-5% MeOH in DCM to give the titlecompound as a white solid (68 mg). δH (CDCl₃) 7.44-7.20 (8H, m), 7.04(2H, d, J 9 Hz), 6.51 (1H, d, J 10 Hz), 4.15-4.03 (4H, m), 3.68 (4H, m),2.79 (2H, t, J 6 Hz), 2.54 (4H, m), 1.05 (3H, t, J 7 Hz). LCMS (ES⁺) RT2.53 minutes, 505 (M+H)⁺.

EXAMPLE 93 Ethyl6-oxo-3,7-diphenyl-4,5,6,7-tetrahydrothieno[2,3-b]pyridine-2-carboxylate

[0411] Hydrogen at 20 to 25 bar was applied to a mixture of the compoundof Example 1 (185 mg), 10% ruthenium on carbon (64 mg) and EtOH (25 mL)stirred at 60 to 90° for 30 hours. The mixture was filtered to removethe catalyst and the filter was washed with EtOH (70 mL). The solutionwas concentrated in vacuo to give a crude product. This was purified bypreparative HPLC (0.08% formic acid in acetonitrile, pH2, Luna 2 C18 5μm 250 mm) to give the title compound as a white solid (48 mg, 26%). δH(CDCl₃) 7.59-7.48 (3H, m), 7.47-7.36 (5H, m), 7.30 (2H, dd, J 8.5, 2.1Hz), 4.10 (2H, q,J 7.3 Hz), 2.84 (2H, m), 2.75 (2H, m), 1.10 (3H, t, J7.3 Hz). LCMS RT 4.1 minutes, 378 (M+H)⁺

EXAMPLE 947-(4-Methoxybenzyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile

[0412] Sodium hydride (24 mg of 60% w/w dispersion in oil, 0.6 mmol) wasadded to a solution of Intermediate 12 (126 mg, 0.5 mmol) in dry DMF (4mL) and stirred at r.t. for 10 mins under nitrogen. 4-Methoxybenzylchloride (68 μL, 0.5 mmol) was added and the reaction mixture heated to60° for 2 hours. The reaction was allowed to cool to r.t. and waspartitioned between EtOAc (75 mL) and brine (50 mL). The organic layerwas dried (Na₂SO₄), concentrated in vacuo and the crude product purifiedby column chromatography (silica, 10% EtOAc in DCM) to give the titlecompound as a white solid (93 mg, 50%). δH (CDCl₃) 7.48 (1H, d, J 9.6Hz), 7.42-7.33(5H, m), 7.26 (2H, d, J 8.8 Hz), 6.77 (2H, d, J 8.8 Hz),6.55 (1H, d, J 9.6 Hz), 5.19 (2H, s), 3.68 (3H, s). LCMS (ES⁺) 395(M+H)⁺.

EXAMPLE 95N-Allyl-6-oxo-3.7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0413] To a stirred solution of the compound of Example 59 (174 mg, 0.5mmol) in dry DCM (5 mL) was added allyl amine (29 mg, 0.5 mmol),triethylamine (101 mg, 1 mmol), and a catalytic amount of4-dimethylaminopyridine followed by EDC (96 mg, 0.5 mmol). The reactionmixture was stirred at r.t. for 4 h and then poured into 2M HCl(aq) (20mL). The product was extracted with DCM (2×20 mL) and the combinedorganic fractions dried (MgSO₄), filtered and the solvent removed invacuo. Purification by radial chromatography (silica, EtOAc) gave thetitle compound as a solid (70 mg). δH (CDCl₃) 7.7-7.1 (11H, m), 4.48(1H, d, J 10 Hz), 5.6-5.4 (1H, m), 5.28 (1H, bs), 4.84 (1H, dd, J 10, 1Hz), 4.69 (1H, dd, J 10, 1 Hz), 3.8-3.6 (2H, m). LCMS (ES⁺) 387 (M+H)⁺.

EXAMPLE 96N-(2,3-dihydroxypropyl)-6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0414] To a stirred solution of the compound of Example 95 (50 mg) in8:1 acetone-water (10 mL) was added 4-methylmorpholine N-oxide (100 mg)followed by a catalytic amount of OsO₄. The reaction mixture was stirredfor 16 h and then poured into saturated NaHCO₃ solution (20 mL). Theproduct was extracted with DCM (2×20 mL) and the combined organicfractions dried over MgSO₄, filtered and solvent removed in vacuo. Thecrude product was purified by column chromatography (silica, 10% EtOH inDCM) to give the title compound as a solid (32 mg). δH (CDCl₃) 7.8-7.1(11H, m), 6.44 (1H, d, J 10 Hz), 5.62 (1H, bs), 3.7-3.1 (5H, m). LCMS(ES⁺) 421 (M+H)⁺.

EXAMPLE 97(6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)-urea

[0415] To a stirred solution of the monohydrochloride salt of thecompound of Example 81 (0.177 g, 0.5 mmol) in dry pyridine (5 mL) wasadded excess trimethylsilyl isocyanate and the reaction stirred at r.t.for 16 h. The reaction was poured onto 2M HCl(aq) (20 mL) and extractedwith DCM (2×20 mL). The combined organic fractions were dried overMgSO₄, filtered and solvent removed in vacuo. The crude product waspurified by radial chromatography (silica, EtOAc) to give the titlecompound as a solid (6 mg). δH (DMSO-d6) 8.78 (1H, s), 7.8-7.55 (5H, m),7.5-7.4 (6H, m), 6.48 (1H, d, J 10 Hz), 6.32 (2H, bs). LCMS (ES⁺) 362(M+H)⁺.

EXAMPLE 981-Ethyl-3-(6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)-urea

[0416] The title compound was prepared from the HCl salt of the compoundof Example 81 and ethyl isocyanate following the method described forthe compound of Example 97 to give the product as a solid (24 mg). δH(DMSO-d6) 8.59 (1H,s), 7.8-7.4 (11H, m), 6.67 (1H, t, J 5 Hz), 6.38 (1H,d, J 10 Hz), 3.1-2.9 (2H, m), 0.97 (3H, t, J 7 Hz). LCMS (ES⁺) 390(M+H)⁺.

EXAMPLE 991-(2-Hydroxyethyl)-3-(6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridin-2-yl)-urea

[0417] To a stirred suspension of the monohydrochloride salt of thecompound of Example 81 (177 mg, 0.5 mmol) in dry DCM was added phosgene(0.26 mL of 1.93M solution in toluene, 0.5 mmol), followed bytriethylamine (101 mg, 1.0 mmol). The reaction was stirred for 1 h atr.t. before adding more triethylamine (51 mg, 0.5 mmol) and ethanolamine(31 mg, 0.5 mmol). The reaction was stirred for a further hour and thenpoured into saturated NaHCO₃(aq) (20 mL). The product was extracted withDCM (2×20 mL), the combined organic fractions dried over MgSO₄, filteredand the solvent removed in vacuo. The crude product was purified byradial chromatography (silica, EtOAc) to give the title compound as asolid (34 mg). δH (DMSO-d6) 8.84 (1H,s), 7.8-7.3 (11H, m), 6.85 (1H, t,J 5 Hz), 6.41 (1H, d, J 10 Hz), 4.69 (1H, t, J 5 Hz), 3.4-3.2 (2H, m),3.1-2.9 (2H, m). LCMS (ES⁺) 406 (M+H)⁺.

EXAMPLE 1006-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-sulfonic acidmethylamide

[0418] To a solution of Intermediate 13 (32 mg, 0.085 mmol) in DCM (5mL) was added methylamine (40% solution in water, 0.17 mmol, 0.1 mL) andthe reaction stirred at r.t. for 18 h. The reaction was partitionedbetween DCM and saturated NaHCO₃(aq) and the DCM layer dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography (silica, EtOAc) to give the title compound as anoff-white solid (10 mg). δH (CDCl₃) 7.71 (2H, dt, J 8.5, 1.8 Hz), 7.73(1H, d, J 9.6 Hz), 7.48-7.62 (5H, m), 7.40 (2H, m), 6.86 (1H, s), 6.63(1H, d, J 9.6 Hz), 4.41 (1H, q, J 5.3 Hz), 2.68 (3H, d, J 5.3 Hz). LCMS(ES⁺) RT 3.14 minutes, 397 (M+H)⁺.

EXAMPLE 1016-Oxo-6,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-sulfonic acidpyrrolidine amide

[0419] The title compound was prepared from Intermediate 13 (18 mg) andpyrrolidine (0.1 mL) following the method described for the compound ofExample 100 to give the product as an off-white solid (4 mg). δH (CDCl₃)7.89 (2H, m), 7.74 (1H, d, J 9.6 Hz), 7.48-7.60 (5H, m), 7.40 (2H, m),6.87 (1H, s), 6.64 (1H, d, J 9.6 Hz), 3.24 (4H, m), 1.77 (4H, m). LCMS(ES⁺) RT 3.47 minutes, 437 (M+H)⁺.

EXAMPLE 1027-[4-(2-Morpholinoethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine

[0420] The compound of Example 92 (91 mg, 0.18 mmol) was dissolved indioxane (1 mL) and 4M HCl(aq) (1 mL) added and the mixture heated atreflux for 48 h. The reaction was partitioned between 2M NaOH(aq) andTHF and the combined THF layers were dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by columnchromatography (silica, 0-10% MeOH in EtOAc) to give the title compoundas an off-white solid (73 mg, 94%). δH (CDCl₃) 7.74 (1H, d, J 9.6 Hz),7.33-7.28 (7H, m), 7.05-7.01 (2H, m), 6.75 (1H, s), 6.58 (1H, d, J 9.6Hz), 4.12 (2H, t, J 5.7 Hz), 3.76-3.67 (4H), m), 2.78 (2H, t, J 5.7 Hz),2.56-2.52 (4H, m). LCMS (ES⁺) RT 2.46 minutes, 433 (M+H)⁺.

EXAMPLE 1037-[4-(2-Morpholinoethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylicacid

[0421] A mixture of the compound of Example 92 (230 mg, 0.46 mmol),sodium hydroxide (91 mg, 2.28 mmol) and EtOH (5 mL) was heated at refluxfor 18 h. EtOH was removed in vacuo and the residue treated with 2MHCl(aq) (2 mL) to give a white solid. The reaction was diluted withwater and then freeze dried. The resultant solid was extracted withisopropanol and the extracts concentrated in vacuo to give the titlecompound as a white solid (97 mg). δH (DMSO-d6) 7.62-7.37 (8H, m),7.21-7.16 (2H, m), 6.50 (1H, J 9.6 Hz), 4.20 (2H, t, J 5.7 Hz),3.62-3.59 (4H, m), 2.76 (2H, t, J 5.7 Hz), 2.54-2.51 (4H, m). LCMS (ES⁺)RT 2.35 minutes, 477 (M+H)⁺.

EXAMPLE 1047-[4-(2-Morpholinoethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0422] To a suspension of the compound of Example 103 (120 mg, 0.25mmol) in dry DMF (3 mL) was added 1,1′-carbonyidiimidazole (41 mg) andthe reaction stirred for 1 h. A further portion of1,1′-carbonyldiimidazole (5 mg) was added and the reaction stirred for30 mins before adding aqueous ammonia (1.5 mL of 25% solution). Thereaction was stirred for 2 h and then was diluted with water (20 mL).The product was extracted with EtOAc (2×15 mL) and the combined organicextracts washed with water (×2), brine (×2) and dried over MgSO₄.Solvent was removed in vacuo to give the title compound as a solid (128mg). δH (CDCl₃) 7.52-7.49 (3H, m), 7.40-7.18 (5H, m), 7.10-7.00 (2H, m),6.51 (1H, d, J 9.6 Hz), 5.34 (2H, bs), 4.12 (2H, t, J 5.7 Hz), 3.71-3.67(4H, m), 2.79 (2H, t, J 5.7 Hz), 2.56-2.53 (4H, m). LCMS (ES⁺) RT 2.28minutes, 476 (M+H)⁺.

EXAMPLE 1057-[4-(2-Morpholinoethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile

[0423] To a solution of the compound of Example 104 (128 mg, 0.27 mmol)in dry DCM (1.5 mL) was added pyridine (44 μL, 0.54 mmol) followed bytrifluoroacetic anhydride (46 μL, 0.32 mmol). TLC showed the reactionwas complete after 5 minutes and the reaction was then diluted with DCM(20 mL) and washed with 2M NaOH(aq) (20 mL). The DCM layer wasseparated, dried (MgSO₄), filtered and concentrated in vacuo. Theresultant residue was co-evaporated with toluene (2×15 mL) to give thetitle compound as a solid (73 mg). δH (CDCl₃) 7.62 (1H, d, J 9.7 Hz),7.51-7.45 (5H, m), 7.29-7.26 (2H, m), 7.08-7.04 (2H, m), 6.62 (1H, d, J9.7 Hz), 4.14 (2H, t, J 5.6 Hz), 3.71-3.68 (4H, m), 2.81 (2H, t, J 5.6Hz), 2.58-2.54 (4H, m). LCMS (ES⁺) RT 2.47 minutes, 458 (M+H)⁺.

EXAMPLE 106 Ethyl7-[4-(2,3-dihydroxypropoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0424] A mixture of the compound of Example 89 (680 mg, 1.74 mmol),2,2-dimethyl-1,3-dioxalan-4-ylmethyl ptoluenesulfonate (600 mg, 2.09mmol), and caesium carbonate (680 mg, 2.09 mmol) in DMF (3 mL) washeated at 80° for 18 h. The reaction mixture was cooled and thenpartitioned between DCM (30 mL) and water (30 mL). The aqueous layer wasextracted with two further portions of DCM (10 mL) and the combinedorganic layers washed with brine, dried (MgSO₄) and concentrated invacuo. The crude product was purified by column chromatography (silica,10-15% EtOAc in DCM) to give ethyl7-[4-(2,2-dimethyl-[1,3]dioxan-4-ylmethoxy)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylateas a white solid (474 mg, 54%). δH (CDCl₃) 7.52-7.43 (8H, m), 7.25-7.20(2H, m), 6.67 (1H, d, J 9.6 Hz), 4.66-4.58 (1H, m), 4.32-4.01 (5H, m),1.58 (3H, s), 1.51 (3H, s), 1.22 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.99minutes, 505 (M+H)⁺. This intermediate (450 mg) was dissolved in EtOH(10 mL) and a catalytic amount of Dowex® 50WX4-200 resin in H⁺ form wasadded followed by water (1 mL). The reaction was heated at 50° overnightand then diluted with EtOH (10 mL) and filtered hot to remove Dowex®resin. The filtrate was concentrated in vacuo to give the title compoundas an off-white solid (388 mg). δH (CDCl₃) 7.60-7.38 (8H, m), 7.27-7.24(2H, m), 6.72 (1H, d, J 9.6 Hz), 6.30-4.23 (5H, m), 4.03-3.89 (2H, m),1.26 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.18 minutes, 488 (M+Na)⁺, 466(M+H)⁺.

EXAMPLE 1077-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0425] To a solution of the compound of Example 91 (134 mg, 0.27 mmol)in EtOH (0.5 mL) and water (0.73 mL) was added sodium hydroxide (0.27 mLof a 1M solution, 0.27 mmol) and the mixture heated at reflux for 5 h.The reaction was freeze dried to give7-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylicacid as a solid. LCMS (ES⁺) RT 2.34 minutes, 472 (M+H)⁺. This compoundwas dissolved in DMF (2 mL) and thionyl chloride (30 μL, 0.405 mmol) wasadded and the reaction stirred at r.t. for 5 mins. Aqueous ammonia (2 mLof a 25% solution) was added and the reaction stirred for 30 mins. Thereaction was diluted with water (20 mL) and extracted with EtOAc (3×30mL). The combined EtOAc extracts were washed with water (2×10 mL), brine(20 mL), dried (MgSO₄) and concentrated in vacuo to give the titlecompound as a solid (104 mg, 82%). δH (CDCl₃) 7.52-7.48 (3H, m),7.37-7.33 (2H, m), 7.29-7.26 (2H, m), 7.20-7.18 (1H, m), 7.01-6.96 (3H,m), 6.90-6.88 (2H, m), 6.50 (1H, d, J 9.6 Hz), 4.23-4.20 (4H, m), 2.42(3H, s). LCMS (ES⁺) RT 2.28 minutes, 471 (M+H)⁺.

EXAMPLE 1087-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile

[0426] To a suspension of the compound of Example 107 (93 mg, 0.20 mmol)and pyridine (32 μL, 0.4 mmol) in DCM (1 mL) was added trifluoroaceticanhydride (34 μL, 0.24 mmol) and the reaction stirred at r.t. for 30mins. A further 60 μL of trifluoroacetic anhydride was added and thereaction stirred for 18 h before being diluted with DCM (10 mL) and THF(5 mL). The mixture was washed with 2M NaOH(aq), brine and the organiclayer separated and dried over MgSO₄. Solvent was removed in vacuo andthe residue purified by column chromatography (silica, 2-5% MeOH in DCM)to give the title compound as a solid (60 mg, 67%). δH (CDCl₃) 7.62 (1H,d, J 9.7 Hz), 7.51-7.44 (5H, m), 7.30-7.27 (2H, m), 7.01-6.98 (2H, m),6.89 (2H, d, J 0.9 Hz), 6.61 (1H, d, J 9.7 Hz), 4.30-4.20 (4H, m), 2.43(3H, s). LCMS (ES⁺) RT 2.46 minutes, 453 (M+H)⁺.

EXAMPLE 1097-{4-[2-(2-Methyl-1H-imidazol-1-yl)ethoxy]phenyl}-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine

[0427] To a solution of the compound of Example 91 (60 mg, 0.12 mmol) indioxane (1 mL) was added 4M HCl(aq) (1 mL) and the mixture heated atreflux for 48 h. Reaction was diluted with 2M NaOH(aq) (5 mL) andextracted with DCM (2×10 mL). The combined DCM extracts were dried(MgSO4), filtered and concentrated in vacuo. The resultant solid wasdried at 60° in a vacuum oven to afford the title compound (32 mg, 62%).δH (CDCl₃) 7.76 (1H, d, J 9.6 Hz), 7.42-7.30 (6H, m), 7.00-6.92 (4H, m),6.76 (1H, s), 6.58 (1H, d, J 9.6 Hz), 4.26-4.20 (4H, m), 2.46 (3H, s).LCMS (ES⁺) RT 2.48 minutes, 428 (M+H)⁺.

EXAMPLE 110 Ethyl7-[4-(2-methyl-1H-imidazol-1-ylmethyl)phenyl]-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0428] To a suspension of the compound of Example 88 (130 mg, 0.32 mmol)in THF (2 mL) was added NaH (14 mg of 60% dispersion in oil, 0.35 mmol).DMF (0.5 mL) was added to aid solubility and the reaction was stirredfor 1 h. Thionyl chloride (25 μL, 0.35 mmol) was added to the reactionmixture cooled in an ice-bath. The mixture was stirred in the ice-bathfor 30 mins before quenching the reaction with water (20 mL) andbasifying with NaHCO₃(aq). The product was extracted into DCM (2×15 mL)and the combined DCM layers dried over MgSO₄, filtered and concentratedin vacuo to give ethyl7-(4-chloromethylphenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylateLCMS (ES⁺) RT 3.97 minutes, 424 (M+H)⁺. To a solution of this compoundin DMF (1 mL) was added 2-methylimidazole (13 mg, 0.16 mmol) and caesiumcarbonate (52 mg, 0.16 mmol) and the mixture heated at 80° for 3 h. DMFwas removed in vacuo and the residue purified by column chromatography(silica, 40-100% EtOAc in isohexane followed by 5% MeOH in DCM) and alsomass directed hpic to give the title compound as a solid (3 mg). δH(MeOH-d4) 7.47-7.27 (10 H, m), 7.06 (1H, d, J 1.4 Hz), 6.82 (1H, d, J1.4 Hz), 6.50 (1H, d, J 9.6 Hz), 5.26 (2H, s), 4.00 (2H, q, J 7.1 Hz),2.28 (3H, s), 0.99 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 2.53 minutes, 470(M+H)⁺.

EXAMPLE 111 Ethyl7-(4-bromophenyl)-3-(2,4-difluorophenyl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0429] To an oven dried flask was added in sequence 4-bromophenylboronicacid (4.2 g, 20.88 mmol), DCM (100 mL), pyridine (1.7 mL), Intermediate14 (3.5 g, 10.44 mmol), copper(II) acetate (3.8 g, 20.88 mmol) andpyridine N-oxide (992 mg). The reaction was stirred at room temperaturefor 7 days with the exclusion of moisture. A further equivalent each ofCu(OAc)₂, pyridine N-oxide and pyridine was added and reaction stirredfor 20 h. The reaction was then diluted with DCM (100 mL), washed with2M HCl(aq), NaHCO₃ (aq), dried (MgSO₄) and concentrated in vacuo. Thecrude product was purified by chromatography on silica (0-3% THF in DCM)to give the title compound as an off-white solid (1.03 g). LCMS (ES⁺) RT4.13 minutes, 489 (M+H)⁺.

EXAMPLE 112 Ethyl3-(2,4-difluorophenyl)-7-[4-(4-methylpiperazin-1-yl)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylatehydrochloride

[0430] The title compound was prepared from the compound of Example 111(1.0 g, 2.04 mmol) and N-methylpiperazine (230 μL, 2.45 mmol) followingthe analogous procedure described for the compound of Example 58. Thecrude product was purified by column chromatography (silica, 1% NH₃(aq)10% MeOH 90% DCM) to give the product as a yellow solid (320 mg). Thissolid was dissolved in DCM and treated with 4M HCl(aq). Solvent wasremoved in vacuo and the residue re-dissolved in hot DCM. The solutionwas allowed to cool and the resultant solid collected by filtration togive the title compound as an off-white solid (310 mg). δH (DMSO-d6)7.66-7.52 (5H, m), 7.39-7.33 (3H, m), 6.67 (1H, d, J 9.6 Hz), 4.10 (2H,q, J 3.1 Hz), 3.50-3.10 (8H, m), 2.94 (3H, s), 1.19 (3H, q, J 3.1 Hz).LCMS (ES⁺) RT 2.57 minutes, 510 (M+H)⁺.

EXAMPLE 1133-(2,4-Difluorophenyl)-7-[4-(4-methylpiperazin-1-yl)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine

[0431] To a solution of the compound of Example 112 (310 mg, 0.61 mmol)in dioxane (35 mL) was added 4M HCl(aq) (20 mL) and the mixture heatedat reflux for 18 h. Reaction had not reached completion and so a fewdrops of concentratedHCl were added and reflux continued for 5 h. Thereaction was quenched with saturated Na₂CO₃(aq) and extracted with DCM(×3). The combined DCM extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product contained a small amount ofresidual ester starting material. The product was therefore dissolved inEtOH (15 mL) and heated at reflux with NaOH (50 mg) for 16 h. Solventwas removed in vacuo and the residue partitioned between DCM andsaturated Na₂CO₃(aq). The DCM layer was washed with Na₂CO₃(aq) (×3),dried (Na₂SO₄) and concentrated in vacuo to give the pure title compoundas an off-white solid (280 mg). δH (DMSO-d6) 8.10-7.95 (2H, m), 7.86(1H, dt, J 9.5, 2.6 Hz), 7.74-7.63 (4H, m), 7.55-7.52 (2H, m), 6.92 (1H,d, J 9.5 Hz), 3.72-3.67 (8H, m), 2.67 (3H,s). LCMS (ES⁺) RT 2.47minutes, 438 (M+H)⁺.

EXAMPLE 114 1,4-Diphenyl-1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one

[0432] Intermediate 17 (230 mg, 1.1 mmol) copper(II) acetate (22 mg,0.11 mmol), pyridine N-oxide (209 mg, 3.3 mmol), and phenyl boronic acid(344 mg, 2.2 mmol) were suspended in DCM (5 mL) and treated withpyridine (0.33 mL, 3.3 mmol). The reaction was stirred at r.t. foreighteen hours, further copper(II) acetate (415 mg, 2.08 mmol) was addedand the reaction stirred for a further four hours. The reaction mixturewas diluted with DCM, washed with ammonium chloride solution, separated,dried and concentrated in vacuo. Chromatography (ethyl acetate-silica)gave the title compound. δH (DMSO-d6) 7.75 (1H, d, J 9.6 Hz), 7.57-7.34(11H, m), 6.20 (1H, d, J 9.6 Hz), 5.66 (1H, dd, J 0.6, 3.1 Hz). LCMS(ES⁺) RT 3.278 minutes, 287(M+H)⁺.

EXAMPLE 1154-(4-Methoxyphenyl)-1-phenyl-1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one

[0433] The title compound was prepared from 4-methoxyphenylboronic acidand Intermediate 17 following the method described for the compound ofExample 114. δH (DMSO-d6) 7.01 (1H, d, J 9.6 Hz), 7.8-7.6 (6H, m), 7.49(1H, d, J 8.9 Hz), 7.27 (1H, d, J 8.9 Hz), 6.42 (1H, d, J 9.6 Hz), 5.91(1H, d, J 2.8 Hz), 4.01 (3H, s). LCMS (ES⁺) RT 3.299 minutes, 317(M+H)⁺

EXAMPLE 116 Ethyl6-Oxo-3-phenyl-7-pyridin-3-ylmethyl-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate

[0434] To a solution of Intermediate 4 (200 mg, 0.67 mmol) in DMF (5 mL)at 0° was added sodium hydride (60 mg, 1.5 mmol, 60% dispersion inmineral oil) and the solution stirred for 5 minutes.3-(Bromomethyl)-pyridine (202 mg, 0.8 mmol) was added and the reactionheated at 65° for 18 hours. The reaction was poured into saturatedammonium chloride solution and the aqueous phase extracted with EtOAc(×3). The organic phases were dried (MgSO₄), filtered and the solventsremoved in vacuo. Column chromatography (silica, 20% THF in DCM) gavethe title product as an off white solid (110 mg). δH (CDCl₃) 9.00-8.25(2H, bm), 7.76 (1H, d, J 7.8 Hz), 7.40-7.35 (3H, m), 7.32 (1H, d, J 9.2Hz), 7.26-7.18 (3H, m), 6.51 (1H, d, J 9.2 Hz), 5.33 (2H, s), 4.11 (2H,q, J 7.1 Hz), 1.09 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.25 minutes, 391(M+H)⁺

EXAMPLE 117 Ethyl7-(1-Benzyloxycarbonyl-piperidin-4-ylmethyl)-6-oxo-3-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate

[0435] To a solution of Intermediate 4 (1.0 g, 3.35 mmol) in DMF (10 mL)at 0° was added sodium hydride (160 mg, 4.0 mmol, 60% dispersion inmineral oil) and the solution stirred for 5 minutes.N-Benzyloxycarbonyl-4-bromomethylpiperidine (1 g, 4 mmol) was added andthe reaction heated at 65° for 18 hours. The reaction was poured intosaturated ammonium chloride solution and the aqueous phase extractedwith EtOAc (×3). The organic phases were dried (MgSO₄), filtered and thesolvents removed in vacuo. Column chromatography (silica, 0-15% EtOAc inDCM) gave the title product as an off white solid (410 mg). δH (CDCl₃)7.40-7.36 (3H, m), 7.30-7.23 (8H, m), 6.42 (1H, d, J 9.6 Hz), 5.06 (2H,s), 4.28-3.80 (4H, bm), 4.13 (2H, q, J 7.0 Hz), 2.80 (2H, m), 2.26 (1H,m), 1.70 (2H, m), 1.42 (2H, m), 1.12 (3H, t, J 7.0 Hz). LCMS (ES⁺) RT4.24 minutes, 531 (M+H)⁺

EXAMPLE 118 Ethyl6-Oxo-3-phenyl-7-piperidin-4-ylmethyl-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate

[0436] The compound of Example 117 (400 mg) was dissolved in EtOH (20mL) and 10% palladium on carbon (40 mg) added. A hydrogen atmosphere (1atmosphere) was applied and the reaction allowed to stir at ambienttemperature for 18 hours. The reaction was filtered and the solventsremoved in vacuo to give the title product as a white solid (210 mg). δH(CDCl₃) 7.50-7.45 (3H, m), 7.28-7.20 (3H, m), 6.42 (1H, d, J 9.6 Hz),4.12 (2H, q, J 7.1 Hz), 3.98 (2H, d, J 7.4 Hz), 3.05 (2H, m), 2.55 (2H,m), 2.18 (1H, m), 1.60 (2H, m), 1.30 (2H, m), 1.11 (3H, t, J 7.1 Hz).LCMS (ES⁺) RT 2.43 minutes, 397 (M+H)⁺

EXAMPLE 119 Ethyl7-(1-Methanesulfonyl-piperidin-4-ylmethyl)-6-oxo-3-Phenyl-6,7-dihydro-thieno[2,3-b]pyridine-2-carboxylate

[0437] The compound of Example 118 (104 mg, 0.26 mmol) was dissolved inDCM (5 mL) and triethylamine (73 μL) followed bymethanesulphonylchloride (40 μL, 0.28 mmol) added. The reaction wasallowed to stir at ambient temperature for 18 hours. The reaction wasdiluted with brine and extracted with DCM (×3). The organic phases werewashed with saturated NaHCO₃ solution and dried (MgSO₄). The reactionwas filtered and the solvents removed in vacuo to give the title productas a white solid (120 mg). δH (CDCl₃) 7.45-7.30 (3H, m), 7.27-7.10 (3H,m), 6.43 (1H, d, J 9.4 Hz), 4.12 (2H, q, J 7.1 Hz), 4.02 (2H, d, J 7.2Hz), 3.75 (2H, m), 2.70 (3H, s), 2.61 (2H, m), 2.20 (1H, m), 1.82 (2H,m), 1.55 (2H, m), 1.12 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.55 minutes,475 (M+H)⁺

EXAMPLE 120 Ethyl7-(2-nitrophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0438] Sodium hydride (440 mg of a 60% suspension in mineral oil, 11mmol) was added portionwise to a suspension of Intermediate 4 (2.99 g,10 mmol) in DMF (50 mL) at r.t. 1-Fluoro-2-nitrobenzene (1.48 mL, 15mmol) was added and the mixture heated at 80° for 4 days. The reactionwas quenched with a few drops of water and the solvent removed in vacuo.Purification by column chromatography on silica (DCM to 5% MeOH in DCMthen in 2% THF in DCM) gave the title compound (807 mg, 19%) as a yellowsolid. δH (DMSO-d6) 8.44 (1H, dd, J 1.3, 8.2 Hz), 8.17-8.08 (2H, m),8.03-7.98 (1H, m), 7.61-7.57 (4H, m), 7.53-7.50 (2H, m), 6.62 (1H, d, J9.7 Hz), 4.14 (2H, q, J 7.1 Hz), 1.12 (3H, t, J, 7.1 Hz).). LCMS (ES⁺)RT 3.748 minutes, 421.0 (M+H)⁺.

EXAMPLE 121 Ethyl7-(2-aminophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyrldine-2-carboxylate

[0439] A mixture of the compound of Example 120 (455 mg, 1.08 mmol) andpalladium on charcoal (10% Pd wt/wt, 90 mg) in EtOH (20 mL) was stirredunder an atmosphere of hydrogen (balloon) for 45 h. The catalyst wasfiltered off and the filtrate concentrated in vacuo. Purification bycolumn chromatography on silica (3% to 5% THF in DCM) gave the titlecompound as a pale yellow solid (257 mg, 61%). δH (DMSO-d6) 7.59-7.52(3H, m), 7.48-7.44 (3H, m), 7.33-7.28 (1H, m), 7.16 (1H, dd, J 1.5, 7.8Hz), 6.98 (1H, dd, J 1.2, 8.2 Hz), 6.77-6.73 (1H, m), 6.59 (1H, d, J 9.6Hz), 5.33 (2H, br s), 4.12 (2H, q, J 7.1 Hz), 1.12 (3H, t, J 7.1 Hz). ).LCMS (ES⁺) RT 3.581 minutes, 391.0 (M+H)⁺.

EXAMPLE 122 Ethyl7-(2-ethylaminophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0440] Obtained from the compound of Example 120 by the method ofExample 121 using longer reaction times. White solid. δH (DMSO-d6)7.60-7.54 (3H, m), 7.50-7.45 (3H, m), 7.43-7.39 (1H, m), 7.18 (1H, dd, J1.5, 7.7 Hz), 6.93 (1H, d, J 7.7 Hz), 6.79-6.75 (1H, m), 6.59 (1H, d, J9.6 Hz), 5.47 (1H, t, J 5.8 Hz), 4.13 (2H, q, J 6.9 Hz), 3.18 (2H, qn, J6.7 Hz), 1.13 (3H, t, J 7.0 Hz), 1.11 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT3.947 minutes, 419.1 (M+H)⁺.

EXAMPLE 1237-(2—Nitrophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylicacid

[0441] A mixture of the compound of Example 120 (150 mg, 0.357 mmol) andlithium hydroxide monohydrate (30 mg, 0.714 mmol) in dioxane (3 mL) andwater (3 mL) was heated under reflux for 1.5 h. The dioxane was removedin vacuo, the aqueous residue acidified (2M HCl) and the precipitatefiltered off and dried to give the title compound as a pale orange solid(112 mg, 80%). δH (DMSO-d6) 13.06 (1H, br s), 8.29 (1H, dd, J 1.3, 8.2Hz), 8.02-7.93 (2H, m), 7.88-7.84 (1H, m), 7.46-7.35 (6H, m), 6.46 (1H,d, J 9.7 Hz). LCMS (ES⁺) RT 3.137 minutes, 393.0 (M+H)⁺.

EXAMPLE 1247-(2—Nitrophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0442] A mixture of the compound of Example 123 (105 mg, 0.268 mmol) and1,1′-carbonyidiimidazole (65 mg, 0.40 mmol) in DMF (3 mL) was stirred atr.t. for 45 min. Concentrated ammonia solution (1 mL) was added and themixture stirred overnight at r.t. Volatiles were removed in vacuo, theresidue taken up in DCM, washed 2M HCl(aq), dried (Na₂SO₄), andconcentrated in vacuo. Purification by column chromatography on silica(4% MeOH in DCM) gave the title compound as a yellow solid (42 mg). 8H(DMSO-d6) 8.28 (1H, dd, J 1.3, 8.2 Hz), 7.99 (1H, dt, J 1.4, 7.8 Hz),7.92 (1H, dd, J 1.4, 7.8 Hz), 7.87-7.82 (1H, m), 7.54-7.47 (3H, m),7.46-7.37 (3H, m), 6.44 (1H, d, J 9.7 Hz), 6.21 (2H, v br). LCMS (ES⁺)RT 2.997 minutes, 392.0 (M+H)⁺.

EXAMPLE 125 Ethyl7-(2-chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate

[0443] tert-Butyl nitrite (0.145 mL, 1.22 mmol) was added to asuspension of copper (II) chloride (120 mg, 0.894 mmol) in acetonitrile(10 mL) at 0° C. After 10 min, a solution of the compound of Example 121(317 mg, 0.813 mmol) in acetonitrile (5 mL) was added. The mixture wasstirred at 0° for 30 min then warmed to r.t. The solvent was removed invacuo, the residue dissolved in DCM, washed HCl (2M), dried (Na₂SO₄) andconcentrated in vacuo. Purification by column chromatography on silica(2% to 3% THF in DCM) gave the title compound as a yellow solid (163 mg,49%). δH (DMSO-d6) 7.91 (1H, ddd, J 1.7, 7.7 Hz), 7.86-7.83 (1H, m),7.78-7.70 (2H, m), 7.60-7.57 (4H, m), 7.53-7.49 (2H, m), 6.66 (1H, d, J9.7 Hz), 4.13 (2H, q, J 7.1 Hz), 1.11 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT3.944 minutes, 410.0 (M+H)⁺.

EXAMPLE 1267-(2-Chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylicacid

[0444] Obtained from the compound of Example 125 by the method ofExample 123. Off-white solid. δH (DMSO-d6) 13.09 (1H, br s), 7.86-7.82(1H, m), 7.78-7.76 (1H, m), 7.71-7.64 (2H, m), 7.52-7.41 (6H, m), 6.58(1H, d, J, 9.7 Hz). LCMS (ES⁺) RT 3.247 minutes, 381.9 (M+H)⁺.

EXAMPLE 1277-(2-Chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide

[0445] A mixture of the compound of Example 126 (125 mg, 0.328 mmol) and1,1′-carbonyidiimidazole (80 mg, 0.49 mmol) in DMF (3 mL) was stirred atr.t. for 90 min. Concentrated ammonia solution (0.5 mL) was added andthe mixture stirred for 1 h. Volatiles were removed in vacuo. Theresidue was treated with 2M HCl(aq) and the resulting solid filtered offand dried. Purification by column chromatography on silica (3% MeOH inDCM) gave the title compound as a pale brown solid (105 mg, 84%). δH(DMSO-d6) 7.91-7.89 (1H, m), 7.83-7.80 (1H, m), 7.76-7.69 (2H, m),7.66-7.59 (3H, m), 7.56-7.53 (2H, m), 7.51 (1H, d, J 9.7 Hz), 6.62 (1H,d, J 9.6 Hz), 6.2 (2H, br s). LCMS (ES⁺) RT 3.120 minutes, 380.8 (M+H)⁺.

EXAMPLE 1286-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbothioamide

[0446] Hydrogen sulphide was bubbled through a solution of the compoundof Example 77 (539 mg, 1.64 mmol) in pyridine (1 0 mL) and triethylamine(0.5 mL) for 30 minutes. The reaction was left to stand for 60 h at r.t.and then nitrogen bubbled through the mixture to ensure the solution waspurged of H₂S. The solution was diluted with DCM and washed with water(×2), 2M HCl(aq) (×2) and brine. The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo. The crude product was recrystallisedfrom DCM-hexane to give the title compound as a solid (327 mg, 40%). δH(DMSO-d6) 9.70 (1H, s), 7.70-7.47 (9H, m), 7.45 (2H, m), 7.38 (1H, d J9.6 Hz), 6.52 (1H, d, J 9.6 Hz). LCMS (ES⁺) RT 3.33 minutes, 385(M+Na)⁺, 363 (M+H)⁺.

EXAMPLE 1297-(2-chlorophenyl)-6-Oxo-3phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbothioamide

[0447] To a mixture of Lawesson's reagent (26.3 mg, 0.065 mmol) and thecompound of Example 127 (50 mg, 0.13 mmol) was added toluene (10 mL) andthe reaction heated at 110° for 1 h. A further portion of Lawesson'sreagent (52.6 mg, 0.13 mmol) was added and reaction heated for 6.5 h.The reaction was diluted with DCM, washed with water, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica, 5-10% EtOAc in DCM) to give the title compoundas a yellow solid (10 mg, 20%). 8H (MeOH-d4) 7.67 (1H, m), 7.58-7.46(7H, m), 7.40 (3H, m), 6.48 (1H, d, J 9.6 Hz). LCMS (ES⁺) RT 3.41minutes, 397 (M+H)⁺.

[0448] The following assays and animal models can be used to demonstratethe potency and selectivity of the compounds according to the invention.In each assay an IC50 value was determined for each test compound andrepresents the concentration of compound necessary to achieve 50%inhibition.

[0449] Preparation of Activated Human P38α for Inhibitor Assays.

[0450] Purification of Human p38α

[0451] Human p38α, incorporating an N-terminal (His)6 tag, was expressedin baculovirus-infected High-Five™ cells (Invitrogen) according to themanufacturers instructions. The cells were harvested 72 h post-infectionand lysed in phosphate buffered saline (PBS) containing 1% (w/v)β-octylglucoside and Complete, EDTA-free™ protease inhibitors (RocheMolecular Biochemicals). The lysate was centrifuged at 35000×g for 30min at 4 oC. and the supernatant applied to a NiNTA™ column (Qiagen).Bound protein was eluted by 150 mM imidazole in PBS (after a wash with15 mM imidazole in PBS) and directly applied to a HiTrap Q™ column (APBiotech). Bound protein was eluted using a 20 column volume, 0 to 1MNaCl gradient. Fractions containing (His)6-p38 were aliquotted andstored at −70° prior to their activation.

[0452] Preparation of GST-MKK6EE-Containing Lysates

[0453]E. coli (BL21 pLysS) expressing the constituitively activated formof human MKK6 fused with an N-terminal glutathione-S-transferase tag(GST-MKK6EE) were harvested by centrifugation and frozen at −70°. Cellswere lysed by resuspension in {fraction (1/10)}th the culture volume ofPBS containing Complete, EDTA-free™ protease inhibitors followed bysonication on ice for 4×15 sec. Cell debris was removed bycentrifugation at 35,000×g and the resultant supernatant stored inaliquots at −70°.

[0454] Activation of (His)6-p38

[0455] 0.45 mL of purified (His)6-p38 was incubated with 50 μL of theGST-MKK6EE-containing lysate for 30 min at 23° in the presence of 1 mMβ-glycerophosphate, 10 mM MgCl₂ and 9 mM ATP. The extent of activationwas monitored by mass spectrometric detection of thedoubly-phosphorylated form of (His)6-p38, which routinely comprisedgreater than 90% of the final (His)6-p38 preparation. The activated(His)6-p38 was then diluted ×10 in PBS and repurified using the methoddescribed above. The concentration of purified, activated (His)6-p38 wasmeasured by UV absorbance at 280 nm using A280,0.1 %=1.2 and thepreparation stored in aliquots at −70° prior to its use in inhibitorassays.

[0456] P38 Inhibition Assays

[0457] Inhibition of Phosphorylation of Biotinylated Myelin BasicProtein (MBP)

[0458] The inhibition of p38 catalysed phosphorylation of biotinylatedMBP is measured using a DELFIA based format. The assay was performed ina buffer comprising, 20 mM HEPES (pH 7.4), 5 mM MgCl₂ and 3mM DTT. For atypical IC50 determination, biotinylated MBP (2.5 μM) was incubated atroom temperature in a streptavidin-coated microtitre plate together withactivated gst-p38 (10 nM) and ATP (1 μM) in the presence of a range ofinhibitor concentrations (final concentration of DMSO is 2 percent).After fifteen minutes the reaction was terminated by the addition ofEDTA (75 mM). The microtitre plate was then washed with Tris bufferedsaline (TBS), prior to the addition of 100 μl of anti-phospho MBPantibody (mouse) together with europium-labeled anti-mouse IgG antibody.After one hour at room temperature the plate was again washed in TBSfollowed by the addition of Enhancement solution (PerkinElmer Wallac).Fluorescence measurements were performed after a further fifteen minutesat room temperature. IC50 values are determined from the plot of Log₁₀inhibitor concentration (x-axis) versus percentage inhibition of thefluorescence generated by a control sample in the absence of inhibitor(y-axis).

[0459] Purification of Human Peripheral Bood Mononuclear Cells

[0460] Peripheral blood mononuclear cells (PBMC) were isolated fromnormal healthy volunteers. Whole blood was taken by venous punctureusing heparinised vacutainers (Becton Dickinson), diluted 1 in 4 in RPMI1640 (Gibco, UK) and centrifuged at 400 g for 35 min over a Ficoll-paquegradient (Amersham-Pharmacia Biotech, UK). Cells at the interface wereremoved and washed once followed by a low speed spin (250 g) to removeplatelets. Cells were then resuspended in DMEM containing 10% FCS,penicillin 100 units ml⁻¹, streptomycin 50 μg ml⁻¹ and glutamine 2 mM(Gibco, UK).

[0461] Inhibitor Dilutions

[0462] Inhibitor stocks (20 mM) were kept as a frozen solution (−20° C.)in DMSO. Serial dilutions of inhibitors were performed in DMSO as250-times concentrated stocks. Inhibitors were diluted 1 in 250 intotissue culture media, prewarmed to 37° C. and transferred to platescontaining PBMC. PBMC and inhibitors were incubated together for 30 minsprior to addition of LPS. Inhibitors used in whole blood assays wereprepared according to a different regime. Using the same stock solutionserial dilutions of inhibitors were performed in DMSO. Inhibitors werethen diluted 1 in 500 straight into whole blood in a volume of 1 μL.Inhibitor was incubated with whole blood for 30 mins prior to theaddition of LPS.

[0463] LPS Stimulation of PBMC

[0464] PBMC were resuspended at a density of 2×10⁵ cells/well in flatbottomed 96 well tissue culture treated plates. After the addition ofinhibitor cells were stimulated with an optimal dose of LPS (E Colistrain B5:055, Sigma, at a final concentration of 1 μg ml⁻¹) andincubated at 37° C. in 5% CO₂/95% air for 18 hours. TNF-α levels weremeasured from cell free supernatants by sandwich ELISA (BioSource#CHC1751).

[0465] LPS Stimulation of Whole Blood

[0466] Whole blood was taken by venous puncture using heparinisedvacutainers (Becton Dickinson), and 500 μl of blood aliquoted into eachwell of a 24 well tissue culture treated plate. After the addition ofinhibitor cells were stimulated with an optimal dose of LPS (E colistrain B5:055, Sigma, at a final concentration of 1 μg ml⁻¹) andincubated at 37° C. without CO₂ for 18 hours. TNF-α levels were measuredfrom cell free supernatants by sandwich ELISA (BioSource #CHC1751).

[0467] Rat LPS Induced TNF Release

[0468] Male Lewis rats (1 80-200 g) are anaesthetised with Isofluor andinjected i.v. with LPS* in a volume of 0.5 ml sterile saline. After 90minutes blood is collected into EDTA tubes for preparation of plasmasamples. Plasma is stored at −70° C. prior to assay for TNFα bycommercial ELISA.

[0469] Rat CIA

[0470] Female Lewis rats (180-200 g) are anaesthetised with Isofluor andimmunised i.d. at the base of the tail with 2×100 μl of emulsioncontaining 4 mg/ml bovine collagen II in 0.01M acetic acid and Freund'sIncomplete Adjuvant at a ratio of 1:1.

[0471] A polyarthritis develops with onset from about 13 days postsensitisation. The disease is mainly confined to the ankles and isquantified by plethysmometry. Results are expressed as change in pawvolume over time.

[0472] In the p38 inhibitor assay compounds of the invention have IC₅₀values of around 30 μM and below. The more active compounds have IC₅₀values of around 500 nM and below. The compounds of the invention areclearly potent inhibitors of p38 kinase, especially p38α kinase.

1. A compound of formula (1a) or (1b):

wherein: the dashed line represents an optional bond; A is a —N═ atom ora —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))— group; R^(a), R^(b) andR^(c) is each independently a hydrogen atom or an optionally substitutedC₁₋₆alkyl group; X is an —O— or —S— atom or —NH— group or substituted Natom; each Y is independently a N atom or CH group or substituted Catom; n is zero or the integer 1; Alk¹ is an optionally substitutedaliphatic or heteroaliphatic chain L¹ is a covalent bond or a linkeratom or group; Cy¹ is a hydrogen atom or an optionally substitutedcycloaliphatic, polycycloaliphatic, heterocycloaliphatic,polyheterocycloaliphatic, aromatic or heteroaromatic group; Ar is anoptionally substituted aromatic or heteroaromatic group; and the salts,solvates, hydrates and N-oxides thereof; for use in the prophylaxis ortreatment of a p38 kinase mediated disease or disorder.
 2. A compoundaccording to claim 1 for use in the prophylaxis or treatment of acytokine mediated disease or disorder.
 3. A compound according to claim1 for use in the prophylaxis or treatment of an immune or inflammatorydisorder.
 4. A compound according to claim 1 for use in the prophylaxisor treatment of rheumatoid arthritis.
 5. The use of a compound accordingto claim 1 for the manufacture of a medicament for the prophylaxis ortreatment of a disease or disorder according to claims 1 to
 5. 6. Acompound of formula (1a):

wherein: the dashed line represents an optional bond; A is a —N═ atom ora —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))— group; R^(a), R^(b) andR^(c) is each independently a hydrogen atom or an optionally substitutedC₁₋₆alkyl group; X is an —O— or —S— atom or —NH— group or substituted Natom; Y is a N atom or CH group or substituted C atom; n is zero or theinteger 1; Alk¹ is an optionally substituted aliphatic orheteroaliphatic chain L¹ is a covalent bond or a linker atom or group;Cy¹ is a hydrogen atom or an optionally substituted cycloaliphatic,polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic,aromatic or heteroaromatic group; Ar is an optionally substitutedaromatic or heteroaromatic group; and the salts, solvates, hydrates andN-oxides thereof.
 7. A compound according to claim 6 in which Cy¹ is anoptionally substituted cycloaliphatic, polycycloaliphatic,heterocycloaliphatic, polyheterocycloaliphatic, aromatic orheteroaromatic group.
 8. A compound according to claim 6 or claim 7 inwhich X is an —O— or —S— atom.
 9. A compound of formula (1b):

wherein: the dashed line represents an optional bond; A is a —N═ atom ora —N(R^(b))—, —C(R^(b))═ or —C(R^(b))(R^(c))— group; R^(a), R^(b) andR^(c) is each independently a hydrogen atom or an optionally substitutedC₁₋₆alkyl group; each Y is independently a N atom or CH group orsubstituted C atom; n is zero or the integer 1; Alk¹ is an optionallysubstituted aliphatic or heteroaliphatic chain L¹ is a covalent bond ora linker atom or group; Cy¹ is a hydrogen atom or an optionallysubstituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic,polyheterocycloaliphatic, aromatic or heteroaromatic group; Ar is anoptionally substituted aromatic or heteroaromatic group; with theproviso that when the compound of formula (1b) is a compound of formula(1c):

in which each Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl or2-chloro-6-fluoro-4-trifluoromethylphenyl group, L¹ is a covalent bond,n is the integer 1 and Alk¹ is a —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)CH₂—, —CH₂CH═CH—, —CH₂CH═CCl—, —CH₂CC— or —CF₂— chain then Cy¹is other than a hydrogen atom; or in which each Y is a N atom or a CHgroup, Ar is a 3-chloro-5-trifluoromethylpyridin-2-yl group, L¹ is acovalent bond, n is the integer 1 and Alk¹ is a —CH₂—, —CH₂CH₂— or—CH₂CH₂CH₂— chain then Cy¹ is other than a hydrogen atom; or in whicheach Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl or2-chloro-6-fluoro-4-trifluoromethylphenyl group, L¹ is a covalent bondand n is zero then Cy¹ is other than a cyclopropyl group; or in whicheach Y is a N atom or a CH group, Ar is a2,6-dichloro-4-trifluoromethylphenyl,2-chloro-6-fluoro-4-trifluoromethylphenyl or3-chloro-5-trifluoromethylpyridin-2-yl group, L¹ is a covalent bond andn is zero then Cy¹ is other than a hydrogen atom; and with the furtherproviso that when the compound of formula (1b) is a compound of formula(1d):

in which: L¹ is a covalent bond, n is the integer 1 and Alk¹ is a —CH₂—chain then Ar is other than a 3-methyl-5-trifluoromethylpyridin-2-yl,5-trifluoromethylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl,3,5-difluoropyridin-2-yl, 3,5-dichloropyridin-2-yl or2-chloro-4-trifluoromethylphenyl group; and the salts, solvates,hydrates and N-oxides thereof;
 10. A compound according to any one ofclaims 6 to 9 in which Cy¹ is an optionally substituted cycloaliphatic,aromatic or heteroaromatic group.
 11. A compound according to claim 10in which Cy¹ is an optionally substituted phenyl group.
 12. A compoundaccording to any one of claims 6 to 11 in which Ar is an optionallysubstituted phenyl or monocyclic five- or six-membered heteroaromaticgroup.
 13. A compound according to claim 12 in which Ar is an optionallysubstituted phenyl group.
 14. A compound according to any one of claims6 to 13 in which R^(a) is a hydrogen atom or methyl group.
 15. Acompound according to any one of claims 6 to 14 in which L¹ is acovalent bond or an —O— or —S— atom or an —N(R²)— [where R² is ahydrogen atom or a straight or branched alkyl group], —C(O)—, —C(S)—,—S(O)— or —S(O)₂— group.
 16. A compound according to claim 15 in whichL¹ is a covalent bond.
 17. A compound according to any one of claims 6to 16 in which n is zero.
 18. A compound according to any one of claims6 to 17 in which each Y is a CH group or a substituted C atom.
 19. Acompound according to any one of claims 6 to 18 in which the dashed linerepresents a bond and A is a —C(R^(b))═ group.
 20. A compound accordingto claim 19 in which R^(b) is a hydrogen atom.
 21. A compound which is:Ethyl 6-oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;Ethyl 7-cyclopropylmethyl-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate; Ethyl6-oxo-3-phenyl-7-(3-thienyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;Ethyl3-(4-fluorophenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;Ethyl3-(2-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;Ethyl6-oxo-7-phenyl-3-(4-tolyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;Ethyl3-(3-methoxyphenyl)-6-oxo-7-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;6-Oxo-3,7-diphenyl-N-(2-piperidinoethyl)-6,7-dihydrothieno[2,3-b]pyridine-2-carboxamide;6-Oxo-3,7-diphenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carbonitrile;3,7-Diphenylthieno[2,3-b]pyridin-6(7H)-one; Ethyl3-(2,4-difluorophenyl)-7-[4-(4-methylpiperazin-1-yl)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;1,4-Diphenyl-1,4-dihydro-pyrrolo[3,2-b]pyridin-5-one; Ethyl7-(2-chlorophenyl)-6-oxo-3-phenyl-6,7-dihydrothieno[2,3-b]pyridine-2-carboxylate;and the salts, solvates, hydrates and N-oxides thereof.
 22. Apharmaceutical composition comprising a compound according to any one ofclaims 6 to 21 together with one or more pharmaceutically acceptablecarriers, excipients or diluents.